Biochemical markers of bone remodeling: Do the guidelines help?

Referenced below is a citation from the Osteoporosis International journal reviewing 157 articles on biochemical markers of bone remodeling. Researchers concluded that there may be a role for these markers in monitoring response to therapy for osteoporosis, but there are very limited data for markers in selecting specific therapy for individual patients and for fracture prediction. In my opinion, there was limited enthusiasm for each of these items.

The major stumbling blocks were:

the lack of well-developed standards for the assays;
the analytical variability of the assays; and
the limited number of clinical trials in which biochemical markers were the major endpoints.

Additionally, there are potentially important issues that I could not find discussed in the article.

Gain and loss of bone reflects the balance between bone formation and bone resorption and isolated measurement of either a bone formation marker or a bone resorption marker cannot predict loss or gain of bone in an individual patient. In group studies, individual markers can separate fast-losers from slow-losers.

A study to derive an algorithm to determine if bone balance is positive (eg, during therapy for low bone mass or osteoporosis) or negative (eg, during therapy with drugs that have a potential negative effect on the skeleton) could be designed but would probably require several thousand untreated subjects followed annually for 5 to 10 years with a bone density at baseline and after 5 to 10 years — not an easy or inexpensive task.

There are also data from clinical trials suggesting that change in bone mineral density after 2 years of therapy is significantly related to changes in bone markers after just 6 months of therapy.

Lack of standardization of assays is not an issue unique to bone turnover markers nor is analytical variability. This is a problem for many assays in clinical medicine, particularly assays not in routine daily use; however, that is not a good excuse for the lack of standardization.

Analytical variability is a related issue, and this is worsened by diurnal variation in the markers and the influence of food on the bone markers. Again, neither of these “obstacles” is unique to the bone field.

As long as the FDA requires fracture as the endpoint of clinical trials seeking FDA approval of a new osteoporosis drug, there may be no good justification for designing and conducting a clinical trial using a surrogate marker for fractures. It is time for the FDA to consider a surrogate marker for fractures and put osteoporosis drugs in line with other FDA approved “preventive” therapies. All FDA approved osteoporosis therapies not only prevent bone loss, they result in bone gain!

For more information:

Vasikaran S. Osteoporos Int. 2011;22:391-420.