Abstract
Osteoporosis is a major health problem worldwide with a prevalence that is projected to increase further due to the ageing population.
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It is defined as a disease characterized by low bone mass and microarchitectural deterioration of bone tissue, leading to enhanced bone fragility and consequent increase in fracture risk.
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The World Health Organization diagnostic criterion for osteoporosis is a bone mineral density (BMD) measurement equal to or more than 2.5 standard deviations (SD) below the young female (age 20–29 years) reference mean (T-score ≤−2.5 SD).
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Whereas osteoporosis is a silent disease, its clinical consequences result from fractures, especially hip fracture, which accounts for the major direct costs. Several highly effective agents have been developed for the treatment of osteoporosis, which have been shown in clinical trials to reduce the risk of fractures. However, in selecting patients for treatment it needs to be borne in mind that the majority of minimal trauma fractures do not in fact occur in those with osteoporosis but in those with osteopaenia, defined as a femoral neck BMD T-score between −1 and −2.5, and normal BMD, defined as a T-score > −1, due to the much higher prevalence of the latter classifications. Apart from BMD, independent contributors to fracture risk include age, gender and a range of clinical risk factors such as prior fractures, parental hip fracture history, body mass index, ethnicity, smoking, alcohol use, glucocorticoid use, rheumatoid arthritis and secondary osteoporosis. The independent contribution of each of these risk factors for fracture has been quantified, permitting the calculation of absolute risk for an individual patient with the FRAX® tool (
Bone turnover markers (BTMs) in blood and urine have been extensively studied in relation to fracture risk assessment and found to predict fracture risk independently of BMD, but they are currently not included in fracture risk algorithms nor are their use in assessment of patients recommended by many guidelines. 5 Whereas the large biological variations seen in these markers are generally recognized, 6,7 the availability of a number of different markers and their use in different clinical trials and, in many cases, the use of different methods for the same marker, have resulted in the dearth of population-based prospective studies with any single analyte. The lack of data from a large part of the world's populations also limits their international use, with most data coming from Europe and North America. The area where there is most evidence currently available for the use of BTMs in osteoporosis is in monitoring therapy, especially with antiresorptive agents. 8–12 BTMs generally show large and rapid responses to the treatments used for osteoporosis in contrast to the slow and modest increment in BMD. The treatment of postmenopausal osteoporosis with an antiresorptive agent results in an early decrease in bone resorption markers followed by a later decrease in bone formation markers. In contrast, treatment with an anabolic agent such as teriparatide results initially in an increase in bone formation and later in an increase in bone resorption. 13 Changes in BTMs following treatment with antiresorptive agents explain a greater percentage of the fracture risk reduction than does the change in BMD. 11 Also, the effect of change in BTMs is independent of change in BMD. Therefore, there is a sound scientific basis for the use of BTMs in monitoring therapy, although there remains a need for more data in this respect.
A position paper recently released by the joint International Osteoporosis Foundation and International Federation of Clinical Chemistry and Laboratory Medicine (IOF-IFCC) Working Group on Bone Marker Standards has highlighted the hiatuses in our current knowledge of the application of BTMs in the management of osteoporosis, and the need to enlarge the experience of the value of BTMs for fracture risk assessment in population-based studies around the world and in monitoring osteoporosis treatment with different agents. 14 A major recommendation of this Working Group is the proposal for the use of one bone formation marker (serum procollagen type I N propeptide, s-PINP) and one bone resorption marker (serum C-terminal cross-linking telopeptide of type I collagen, s-CTX) as reference analytes in clinical trials as well as in observational studies in order that adequate data be accumulated for their application in clinical practice. 14 Although it is recognized that there is no perfect gold standard marker, the reference standards were chosen based on criteria such as adequate characterization and clear definition of the marker, their specificity to bone and performance in clinical studies, wide availability, biological and analytical variability, sample handling, stability, ease of analysis and availability of method in routine laboratories and the medium of measurement (serum versus urine). Areas that need to be carefully controlled when studying the reference BTMs in future clinical trials include appropriate sample handling, ensuring that BTMs are measured in all available patients in trials and the use of appropriate statistical methods, including an assessment of whether the final BTM level following treatment is a guide to fracture risk. Other possible uses of BTMs which also need further study include the prediction of rate of bone loss, identification of secondary osteoporosis, targeting intervention and improving adherence.
The standardization of measurement of the reference BTMs, which is flagged as a future goal of this working group, should ensure comparability of data across time and space, and help determine universally applicable decision points for each marker. The current lack of interlaboratory agreement of results for BTMs, even where the same method is used for a particular analyte, is well recognized. 15 This makes it difficult to follow a patient by testing in different laboratories, problematic for multicentre clinical trials and impossible to designate cut-points and decision levels in treatment guidelines.
The adoption of reference BTM standards does not preclude the use of other BTMs in clinical studies. Rather, it provides internal references and the ability to pool studies more easily for meta-analyses both for appropriately powered cohort studies so that BTMs can be considered alongside other risk factors for fracture risk calculations and for inclusion in clinical trials to allow study of the relationship between change in BTM and fracture risk reduction.
In conclusion, the IOF-IFCC's position paper, while highlighting the hiatuses in our current knowledge, supports the role of BTMs in the management of patients with osteoporosis. It identifies areas in which further data need to be accumulated and asserts that the adoption of international reference standards by the clinical and scientific community in the field of osteoporosis research will markedly enhance laboratory consistency and facilitate their inclusion in routine clinical practice.
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