Breast cancer patients with bone metastases are characterised by increased levels of nonisomerised type I collagen fragments

BACKGROUND: Fragments of collagen type I containing the epitope AHDGGR (CTX) are generated during bone resorption. The aspartyl-glycine (DG) site within CTX is synthesised in the L-aspartyl peptide (αL) form, but converts to the age-modified forms L-isoaspartyl peptide (βL) and D-aspartyl peptide (αD) over time. The purpose of the present study was to test the ability of the various CTX forms to identify breast cancer patients with bone metastases and to investigate whether such patients had an altered CTX excretion pattern. METHODS: In this cross-sectional study we compared CTX excretion in healthy premenopausal and postmenopausal women with CTX levels in patients with breast cancer. The breast cancer cohort comprised eight hypercalcemic patients with bone metastases (HC+), 100 normocalcemic patients with bone metastases (NC+) and 15 normocalcemic patients without bone metastases (NC-). RESULTS: In HC+ patients and NC+ patients, the excretion of αL CTX was highly increased compared with NC- patients (P < 0.01), with Z scores of 3.4 and 2.0, respectively. The excretion of the age-modified forms (βL and αD CTX) was less increased in HC+ patients and in NC+ patients as compared with NC- patients, with Z scores of 2.2 and 1.0, respectively, for βL CTX, and of 1.6 and 0.8, respectively, for αD CTX. CONCLUSION: Assays for the various isoforms of CTX have different sensitivities to identify patients affected by bone metastases. The αL CTX isoform reflecting resorption of young bone appeared to provide the best differentiation of patients affected by breast cancer-induced bone metastases. In conclusion, patients affected by metastatic bone disease present an altered excretion pattern of CTX isoforms

Investigation of bone disease using isomerized and racemized fragments of type I collagen.

In the collagen type I C-telopeptide an aspartyl-glycine site within the sequence AHDGGR is susceptible to molecular rearrangement. In newly synthesized collagen this site is in the native form, denoted alpha L. During aging a spontaneous reaction occurs resulting in three age-modified forms: an isomerized form (beta L) a racemized form (alpha D), and an isomerized/racemized form (beta D). In this study, we measured the urinary excretion of the four forms of C-telopeptides (CTX) in healthy adults and in patients with bone diseases. Levels of all CTX forms were higher in healthy postmenopausal women (P<0.001) compared with premenopausal controls. Levels decreased within 3 days of bisphosphonate treatment indicating that all CTX forms reflect bone resorption. In hyperthyroidism, characterized by a generalized increased bone turnover, native (alpha L) and age-modified (beta L, alpha D and beta D) forms increased to a similar extent compared to controls, resulting in normal ratios between the alpha L and age-modified forms of CTX. Conversely, in Paget's disease and prostate cancer-induced bone metastases, conditions characterized by focal increased bone turnover, alpha L CTX levels were more elevated than those of age-related CTX forms, resulting in increased ratios between native and age-modified CTX. For example, the ratio alpha L/alpha D was increased 7-fold in Paget's disease (P<0.001) and 2-fold in prostate cancer-induced bone metastases (P<0.002). In conclusion, the study suggests that in conditions with a localized alteration in bone turnover the ratio between alpha L CTX and the age-modified forms is significantly elevated. This may provide a new diagnostic and monitoring tool for diseases such as metastatic bone cancer and Paget's disease.Journal Articleinfo:eu-repo/semantics/publishe