Measurements of biochemical markers of bone turnover have been explored as a diagnostic tool for the detection of osteolysis after THA, but their predictive value in individual subjects has been poor. One explanation for this low diagnostic utility is that the mechanism of bone resorption in osteolysis may be different to that occurring in other high bone turnover states, such as osteoporosis, where these markers were principally developed. The aim of this study was to examine the role of the biomarkers urinary ααCTX-I and serum CTX-MMP, that are released in pathological rather than physiological bone turnover states, for detecting periprosthetic osteolysis in a case control study of 23 subjects with osteolysis and 26 controls. All samples were collected between the hours of 0800 and 1000 following an overnight fast, and were assayed using standard techniques. The demographic characteristics of the subjects in both groups were similar. Serum CTX-MMP was greater in the osteolysis versus the control group (P=0.001). Urinary ααCTX-I was similar between osteolysis and control groups (P> 0.05). A cut-off value of 5.50ng/mL CTX-MMP had a sensitivity of 91% (95% CI: 72 to 99) and specificity of 69% (48 to 96) detecting osteolysis (P=0.001). The same cut-off had a sensitivity of 100% (100 to 100) and specificity of 63% (44 to 79) for detecting femoral osteolysis (P=0.0004), and a sensitivity of 89% (65 to 98) and specificity of 58% (39 to 75) for identifying pelvic osteolysis (P=0.014). Serum CTX-MMP shows promise for further investigation as a sensitive bio-marker for detecting periprosthetic osteolysis.