Publisher Summary Although current biochemical markers have demonstrated clinical utility in the differential diagnosis of metabolic bone diseases and in predicting fracture risk and response to treatment in postmenopausal osteoporosis, they do have some limitations. Current biochemical markers of bone resorption are based primarily on type I collagen, which is not bone-specific but rather widely distributed in several other body tissues. Some of the type I collagen-based bone resorption markers are characterized by significant intra-patient variability, which impairs their use in individual patients. The systemic levels of biochemical markers reflect global skeletal turnover and do not provide distinct information on the remodeling of different bone envelopes, i.e. trabecular, cortical and periosteal. Further, their relative contribution to skeletal turnover may vary with aging, disease and treatment. Finally, current markers mostly reflect quantitative changes of bone turnover and do not provide information on the structural abnormalities of bone matrix properties which are an important determinant of bone fragility, especially toughness. Recently, new biochemical markers have been investigated to address some of these limitations, although their clinical utility in assessment of bone turnover abnormalities in postmenopausal and male osteoporosis is limited.