How Clinically Useful Are Bone Turnover Markers?

Metabolic bone disease is highly prevalent, and although bone turnover marker (BTM) assays have a key role to play in its diagnosis and monitoring, the lack of internationally recognized guidelines for the interpretation of patient results has limited their clinical usefulness.

Patients with osteoporosis, in particular postmenopausal osteoporosis, make up the largest group of BTM assay recipients, where it is used to assess fracture risk and/or to guide therapy and monitor response.

We set up a task force, in collaboration with the International Osteoporosis Foundation, to identify a consensus reference standard BTM. Although we believe in its clinical usefulness, a thorough review of current reports has indicated that there are insufficient data to guide the use of any particular BTM for clinical use, despite the availability of a body of evidence to suggest that they may be useful. For example, of 22 studies that reported on the relationship between a BTM and future risk of fracture, 18 linked elevated BTM level with fracture risk (1). However, the problem is that a number of BTM assays have been used in these studies, so no apparent benefit has been found for any one particular BTM as a bone formation or a bone resorption marker.

Based on our own research of these reports, we agreed that serum beta-CrossLaps (β-CTx) appeared to be a suitable bone resorption marker, and procollagen type 1 amino-terminal propeptide (PINP) was a suitable bone formation marker.

A second working group from the North American National Bone Health Alliance also conducted a review and reached the same conclusions.

We’re now in a position to investigate this further, but we do have some concerns: we are currently investigating whether or not current commercial clinical assays for serum β-CTx and serum PINP provide comparable results. Once we are satisfied that all assays are producing comparable results, we can confidently conduct metaanalyses of clinical trial data where these assays have been used and combine data from all assays used by clinical laboratories.

Our plan is to calculate the discrepancies in measurements for these BTMs across different manufacturers, reagent lot numbers and laboratories. Our goal is to establish the least significant change for each BTM that will allow clinicians to confidently analyze data irrespective of the clinical lab or assay used.

Right now, I admit that it’s not guaranteed that our recommendations will be incorporated into clinical guidelines. A major immediate task is to reduce variation between BTM levels so that only variation in bone turnover is being assessed. If we achieve this first and foremost, the clinical use of BTMs for fracture prognosis can be optimized. However, there is still a lot about the basic physiology of BTMs that is not understood; for example, we know that levels of some BTMs are markedly affected by eating. Initially, this was attributed to calcium consumption, based on the rationale that calcium affected calciotropic hormones and, therefore, indirectly affected bone turnover (2). But more recently, it’s been suggested that gut hormones, such GLP-1, markedly affect serum β-CTx levels (3), while another BTM, osteocalcin, might actually be a hormone that regulates whole energy metabolism of the body (4). If whole energy metabolism is related to BTMs, there will be a great deal of variation between individuals independent of their bone status.

Irrespective of ongoing research, we will not be able to proceed further unless we successfully conduct the studies and harmonization of the assays as planned.