Studies exploring the performance of established and emerging bone biomarkers against histomorphometric assessment of bone turnover are limited and overall yield inconclusive results as to their diagnostic utility. Bone biomarkers, although promising, currently fail to meet the needed diagnostic accuracy to replace bone histomorphometry and thus are not yet ready for clinical use. Bone biomarkers have not only several advantages, but also important limitations such as high biological variability, retention with kidney disease, preanalytical issues, and interassay variability. These important issues must be considered when developing and evaluating bone biomarkers. There is an urgent need for harmonization and standardization of available assays and additional bone biopsy studies.