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The goal of the current study was to identify urinary biomarkers that differentiate total hip replacement patients who eventually develop osteolysis from patients who do not. We used a repository of 24\u2010h urine samples collected prior to surgery and annually thereafter in 26 patients, 16 who developed osteolysis, and 10 who did not. We examined the markers at radiographic diagnosis, annually for 6 years preceding diagnosis, at the first post\u2010operative sampling point, and pre\u2010operatively. Patients in the osteolysis and non\u2010osteolysis groups were matched according to time post\u2010surgery and did not differ in the male:female ratio or age at surgery. Seven candidate biomarkers were measured, including free deoxypyridinoline (DPD), cross\u2010linked N\u2010telopeptides (NTX), interleukin\u20106 (IL\u20106), interleukin\u20108 (IL\u20108), osteoprotegerin (OPG), \u03b1\u2010crosslaps (\u03b1\u2010CTX), and \u03b2\u2010crosslaps (\u03b2\u2010CTX). As an individual biomarker, DPD demonstrated the highest ability to predict osteolysis, with an area under the curve (AUC) in Receiver Operating Characteristic (ROC) analyses of 0.844 at 6 years prior to diagnosis. A panel of \u03b1\u2010CTX and IL\u20106 was able to identify at\u2010risk patients with an AUC of 0.941 or greater at all post\u2010operative time points and an AUC of 1.000 pre\u2010operatively. The results demonstrate the potential of using non\u2010invasive biomarkers to identify patients at risk for peri\u2010implant osteolysis long before the emergence of radiographic signs. Further, the high accuracy of the pre\u2010operative biomarker levels demonstrates the potential importance of pre\u2010existing, patient\u2010specific factors driving subsequent osteolysis. Study Design \u00a9 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. 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