Use of Bone Turnover Markers in the Real World: Are We There Yet?

Early identification of the patient at risk for osteoporosis is pivotal for the effective prevention and management of a condition that, if unrecognized, almost invariably deteriorates, leading to considerable complications such as fractures, chronic pain, immobility, social isolation, and death. Over the years, we have learned that, in addition to the well-known clinical risk factors of osteoporosis, accelerated bone turnover is associated with a higher risk of fracture, independent of age, sex, body weight, disability, and bone mass. Hence, the rate of bone turnover seems to determine aspects of bone strength that are distinct from, and are not captured by the measurement of bone mass, structure or geometry. The last 20 yr have seen considerable progress in the development and validation of serum and urine markers of bone turnover. If applied and interpreted correctly, these indices permit the specific measurement of bone formation or bone resorption without the need of going through the process of a bone biopsy. Today, there is little doubt that markers of bone turnover can be used to estimate fracture risk in both postmenopausal women and older men. However, the real domain for the use of bone turnover markers in clinical practice seems to lie in the monitoring of anti-osteoporotic therapy, treatment efficacy, and patient compliance. In contrast to changes in BMD, which occur slowly and may not be detectable before several years of treatment, biochemical markers of bone turnover change rapidly in response to therapeutic interventions. Based on these findings, and through the intense efforts of commercialization and automatization, ‘‘bone markers’’ are today considered useful tools that many would like to see applied in the diagnosis and management of metabolic bone disease, including osteoporosis. Thus far, however, the productive use of these markers has been confined mostly to research studies or commercial trials, which, as a rule, look at larger populations rather than the individual patient. As a matter fact, most current practice guidelines are very clear in not recommending the use of bone turnover markers in routine clinical practice. The reasons for the apprehensiveness of most independent experts and professional societies in regard to the widespread use of bone turnover markers are 3-fold: first, the variability of nearly all bone markers makes it difficult to apply the results derived from larger trials to individual patients; second, many countries lack pivotal quality control programs for bone turnover markers, including those offered by commercial laboratories—this deficit is further confounded by poor standardization of most assays; and third, the lack of valid reference ranges leaves many clinicians with uncertainties how to interpret a given result. It is in this context that the paper by Glover et al. in this issue of the Journal is of particular interest. Based on an international study of 637 premenopausal women, the investigators aimed to set-up reference intervals for two well-established markers of bone formation (bone alkaline phosphatase [ALP], N-terminal propeptide of type I procollagen [PINP]) and two markers of bone resorption (serum C-terminal telopeptide of type I collagen [S-CTX], urinary N-terminal telopeptide of type I collagen [UNTX]). Premenopausal volunteers eligible to participate were women between the age of 30 and 39 yr with a BMI between 18 and 29 kg/m and without medical conditions known to affect bone metabolism (although some were taking an oral contraceptive pill). All samples were obtained at roughly the same time of the year (in the northern summer) and time of day (i.e., between 8:00 a.m. and 10:00 a.m.) after an overnight fast. The study is strengthened by its relatively large sample size, its reasonably well-characterized study population, and a strict study protocol within the wider context of the HORIZON-PFT trial. Although the authors paid special attention to minimize variability in their study cohorts, serum levels of bone turnover markers (PINP, S-CTX) were found to be different between study centers in the United Kingdom, France, Belgium, and the United States. For instance, women in France showed significantly higher mean levels of S-CTX relative to those living in the United Kingdom and significantly higher mean levels of PINP than women living in Belgium and the United Kingdom. The regional differences observed in this study were in part explained by variations in BMI and lifestyle factors such as smoking habits, use of the oral contraceptive pill, exercise levels, and alcohol consumption. These findings again highlight the clinically important fact that bone marker levels are affected by a number of modifiable and nonmodifiable