Biochemical Markers of Bone Turnover: Why Theory, Research, And Clinical Practice are Still in Conflict (Editorial‪)‬

In metabolic bone diseases other than osteoporosis (Paget disease, rickets and osteomalacia, primary and secondary hyperparathyroidism), biochemical markers of bone turnover have been important clinical tools in patient management for more than 3 decades. In these diseases, bone metabolism is often so abnormal that even crude, nonspecific markers such as total serum alkaline phosphatase and urine hydroxyproline have been sufficiently reliable to allow clinicians to make appropriate management decisions without difficulty or error. When noninvasive measurements of bone mineral density (BMD) became available, the most common metabolic bone disease, osteoporosis, began to receive attention from researchers, pharmaceutical companies, and clinical practitioners. BMD technology from the beginning had very acceptable accuracy and precision errors such that diagnosis and monitoring of disease progression or regression were straightforward (1, 2). However, there was and remains one major drawback to BMD alone in the management of osteoporosis: bone turnover is generally so slow (particularly in relation to the other metabolic bone diseases listed above) that it may take up to 2 years in most circumstances to be certain with 95% confidence that any change in BMD is more than can be accounted for by method imprecision (3-5). When studying large groups of patients in a clinical trial, this is not a practical problem because significant group changes can be detected as early as 6 months after an intervention has been started (6-9). This is of limited benefit to individual patient care. To overcome this, researchers turned to biochemical markers of bone turnover as adjunctive tools in patient management. It became clear very early in this endeavor that total alkaline phosphatase and urine hydroxyproline lacked both the sensitivity and specificity to be of much value. Newer markers had to be developed, which required a more in-depth understanding of basic bone biochemistry and physiology. Over the past 15 years, this challenge was met with rapid development of markers of bone resorption and bone formation that were more specific to bone and bone collagen. We now have a broad array of resorption markers (e.g. pyridinium cross-links of collagen and the amino- and carboxy-terminal telopeptides of these cross-links) and formation markers [e.g., bone-specific alkaline phosphatase (BAP), procollagen extension peptides, osteocalcin]. Much effort has gone into assay development and refinement such that several bone turnover markers are now available on fully automated platforms (10,11).