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Markers of bone turnover are often elevated in patients with prevalent bone metastases (BM). To test whether bone markers may be used as early indicators of developing BM, we prospectively studied 113 women with primary breast cancer. At the time of study inclusion, none of the women had BM, skeletal disease or was on bone active drugs. During follow-up (8-52, median 30 mo.), pt. were seen every 3 mo. and blood/urine specimens were obtained. Eleven patients developed BM (BM+) and each of them was matched to 4 women remaining free of BM (BM-). Markers were serum (s) calcium, sTAP, sBAP, sOC, sPICP, sNTX, sCTX and urinary (u) PYD, uDPD, uNTX, uCTX. All analyses were done in single batches after study end. At any given point in time, marker levels in the BM+ group did not differ from those in the BM- group. Levels at baseline did not predict later BM (OR 0.14-1.01, all ns). 93% of all changes in bone markers were below the least significant change, as defined in an independent group of similar patients. The remaining 7% of values could not be associated in a consistent pattern with the occurrence of BM. We conclude that in patients with primary breast cancer, biochemical markers of bone turnover can not be used to predict or diagnose incident BM. This lack in diagnostic validity is mainly attributable to the high overall and long-term variability of the currently used bone markers.

Variability of bone marker measurements is a major problem in their clinical application. Most studies on marker variability have been performed in healthy subjects and over relatively short intervals of time. We prospectively evaluated the long-term variability of bone markers in 102 postmenopausal women diagnosed with primary breast cancer. During follow up (8-48, median 30 mo.), no patient developed bone metastases or other skeletal disease. Patients were seen every 3 months and exactly timed blood/urine specimens were obtained. All analyses were performed after study end by the same technician, using a single batch of reagents per analyte. The coefficient of variation was calculated as CV (%) = square root(sigma(CVi2)/n) (CVi = SD/mean x 100; n = n of CVi). The least significant change (LSC) was then LSC (%) = Z x CV x square root(2). Z = 1.96 for a 95% confidence interval (LSC-95). In a subset of n = 10 patients with no potential interference during follow-up, lowest CVs were recorded for serum (s) calcium (5%), sTAP (12%) and sBAP (14%). The LSC-95 for these markers were 14%, 33% and 39%, respectively. Highest CVs were seen with urine (56%) and serum (42%) CTX (LSC-95: 155%, 117% resp.). We conclude that in breast cancer patients without bone metastases, long-term variability varied greatly between markers. For certain markers, the LSC seems considerably higher than previously reported.