The use of biochemical markers of bone turnover in osteoporosis: state of the art

The assay features of biochemical markers of bone turnover have markedly improved in the past few years. The most sensitive and specific markers of bone formation include serum bone alkaline phosphatase, total osteocalcin (including the intact molecule and the large N-Mid fragment) and the N extension peptide of type I collagen (PINP) measured with a recently developed radioimmunoassay. Among the various markers of bone resorption, measurements of the urinary excretion of the (deoxy) pyridinoline crosslinks and of N- and C- related telopeptides (NTX and CTX respectively) are the most sensitive and specific ones. In addition, a two-site immunoassay of serum CTX is now widely available. Bone markers can be used to predict the rate of bone loss in postmenopausal women. Three independent studies have shown that high bone turnover is associated with increased bone loss over 4 to 15 years in women aged 50 to 70 years. In addition, we have shown in elderly women that increased bone resorption, i.e. above the premenopausal range, is associated with a two-fold increase in the risk of hip fractures and that those with both a low BMD (T score < -2.5) and increased bone resorption have a 4- to 5- fold increase in hip fracture risk. We have recently confirmed that increased bone turnover predicts the risk of fragility fractures in a younger cohort of postmenopausal women followed for an average of 5 years. The mechanisms underlying the increased bone turnover in some (but not all) postmenopausal women are unknown. The increase appears to be independent from the residual secretion of 17 s estradiol (E2), assessed by a highly sensitive radioimmunoassay. Indeed, we found that a low serum E2 predicts the risk of fragility fractures in late postmenopausal women (but not in the elderly) independently of the rate of bone turnover. Bone markers can be used to monitor the efficacy of antiresorptive therapy such as hormone replacement therapy, raloxifene and bisphosphonates. We and others have shown that the short-term (3 to 6 months) decrease of bone turnover is significantly correlated with the long-term (2 years) increase in BMD of the spine. In addition, the decrease of serum osteocalcin is associated with the risk of vertebral fractures in osteoporotic women treated with raloxifene. Similar studies in patients using alendronate or risedronate show that the short-term decrease of bone turnover markers is correlated with the risk of subsequent fractures. Thus, with adequate cut-offs, individual patients can be monitored with bone markers earlier than with DXA. It remains to be assessed if such a monitoring can improve long-term compliance with therapy.