Biochemical markers of bone turnover in the clinical development of drugs for osteoporosis and metastatic bone disease: potential uses and pitfalls.

Biochemical markers of bone turnover are used increasingly during the clinical development of drugs for the treatment of metabolic bone diseases such as Paget's disease, osteoporosis and cancer that has metastasised to the bone. However, assessing the optimal value of these markers is often complicated, and such an assessment is an obvious prerequisite for rational use of the markers and, consequently, potential improvement of clinical drug development. Biochemical markers of bone turnover are substances in the blood or urine that are produced or released during bone remodelling. They provide semiquantitative information on bone remodelling, and are often the most adequate tool to describe the pharmacodynamics of the drug. Their use has increased considerably because of dose-effect relationships that have been seen with certain drugs, but also because they have proven relationships with clinical outcomes in several metabolic bone diseases. However, there is a lack of information on the kinetics of these markers, and the immunoassays that are frequently used in their monitoring often measure a mixture of fragments rather than a single molecular entity. For drug development it should also be realised that different markers, but also different assays for the same marker, may provide different results, considerably limiting the ability to compare results. In postmenopausal osteoporosis, relationships have been shown between several biochemical markers of bone turnover, and either fracture risk and/or the antifracture efficacy of drugs. Such relationships can be used for the development of drugs with similar mechanisms of action, but also for the development of these drugs for closely related indications, such as corticosteroid-induced osteoporosis. In both of these instances, data on effects on biochemical markers of bone turnover are usually employed in combination with information about effects on bone mineral density. However, the relationships of these parameters with clinical outcomes may be remarkably different for drugs with alternative mechanisms of action, challenging the use of the markers for the development of new drugs for the treatment of patients with osteoporosis. At present, the pharmacological treatment of cancer that has metastasised to the bone is limited to several bisphosphonates. Recent studies have shown relationships between the normalisation of levels of biochemical markers of bone turnover and clinical outcomes, and prospective studies investigating the application of such relationships are ongoing. The markers may play an important role in the optimisation of registered bisphosphonate treatments. However, their role in the development of new drugs is still limited to dose selection, and potential relationships with clinical outcomes remain to be investigated in instances of new mechanisms of action. Biochemical markers of bone turnover are a valuable asset for drug development, but their rational use is determined by a number of variables. Correctly manipulating these may improve clinical development of drugs for the treatment of patients with metabolic bone diseases such as osteoporosis and cancer metastatic to the bone.