Biochemical markers of bone turnover have been proposed to monitor the response to bisphosphonate therapy for osteoporosis, but this requires true between-person differences in the response to therapy. Using mixed models we analyzed three annual measurements of two markers (bone alkaline phosphatase [BAP] and cross-linked N-telopeptide of type I collagen [NTX]) from the Fracture Intervention Trial. We compared marker variation among women allocated to alendronate with that among women allocated to placebo to estimate how much variation was due to true between-person differences in response to treatment, and how much was due to random within-person fluctuations unrelated to treatment. For both markers we found that the mean effect of treatment differed by the baseline level of the marker. After allowing for this and other effects, we found large true between-person differences in response to treatment for both markers, with a coefficient of variation (CV) for NTX of 25.1% and for BAP of 21.2%. However, random within-person fluctuation was even larger, with a CV for change in NTX of 42.5% and for change in BAP of 25.8%. Although repeated measurements have the potential to reduce within person variability, even triplicate baseline marker measurements resulted in an averaged value that was only within 31% of the true value with 95% certainty. In summary, although bone turnover markers appear promising for monitoring between-person differences in response to treatment, their use in clinical practice is currently limited by large random within-person variation.