Bone is a plastic tissue

Decades ago, medical school final exams took the form of essays rather than the current multiple choice questions. For the histology finals, I selected the topic “Bone is a plastic tissue.” I knew absolutely nothing about the skeleton other than it was brittle and broken. It turns out that not only was I wrong but I knew as little about it as the professors: for the one and only time in medical school, I topped the class.

Bone is clearly a plastic tissue subject to modeling during growth and development and remodeling shortly after epiphyseal closure. The most common skeletal disease resulting from altered remodeling is osteoporosis in which resorption outstrips formation. Monitoring resorption and formation — measures of total skeletal metabolism — is overlooked in favor of monitoring bone mineral density — measures of regional, not total, skeletal status.

Why bring this up now?

A PubMed search for the last 10 years returned 35,121 citations (275 meta-analyses) for “bone density” and 13,162 citations (28 meta-analyses) for “bone turnover markers”. There is clearly no shortage of peer-reviewed literature regarding bone turnover markers, but there is so much variability in those 13,162 citations that meaningful consensus data is lacking.

You don’t need reminding that adherence to oral medications for osteoporosis is low, and not that great for injectable (subcutaneous or IV) therapies. Several studies have examined the use of markers to improve medication adherence but, to my knowledge, none of them have found markers to be useful in maintaining compliance with therapy.

Bone turnover markers have no role in determining which patient is a candidate for osteoporosis therapy and have not had much effect on patient adherence to therapy. My own practice is to measure markers as I recommend the patient start therapy and re-check markers after 6 months of therapy to both monitor that the therapy is effective and that the patient is adherent to therapy. My success rate in the latter is no better than reported in the literature.

I repeat measurement of markers when serial measurement of BMD indicates that BMD is no longer increasing. Ongoing use of osteoporosis therapies is safe for the vast majority of patients in whom BMD has plateaued, but there is increasing awareness of atypical femoral shaft fractures in a small minority of patients on long-term antiresorptive therapy. With that in mind, I interrupt therapy in patients with stable BMD, where bone turnover markers are in the bottom quartile of the reference interval. I re-check them at 6 monthly intervals until the values get to the top half of the reference interval, at which time therapy is re-started. That happens infrequently. When allowed by insurance coverage, I repeat BMD measurement after 1 year off therapy but have yet to see a patient in whom BMD has declined during that year. I cannot recall a patient in whom an uptick in remodeling has not occurred within 2 years without antiresorptive therapy and use that as an indication to re-start treatment.

Which markers to use? My preference is or serum CTX (resorption) and P1NP (formation) because patients are never in a hurry to provide a 24-hour urine collection or even a fasting urine sample.

Much has been written about the diurnal variation of biochemical markers of bone remodeling and the intra- and interassay variability. These are specious arguments against serial measurements of bone turnover markers. Firstly, when remodeling is suppressed as a result of therapy, even 50% variability in markers (it is not that variable) does not move many patients from one quartile to another. Secondly, there are many laboratory tests in which the variability is the same or even worse than for bone turnover markers. That has not stopped any clinician I know from continuing to order and rely on those results.

The bottom line — patient adherence to therapy tests our skills as clinicians every day. Asking a patient to wait 2 years to see if the therapy we prescribe is effective or not makes little sense to me.