Review
Bone turnover markers in the management of postmenopausal osteoporosis

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Abstract

Osteoporosis is the most common cause of fragility fractures. Bone remodelling is essential for repairing damaged areas within bone to preserve bone strength and for assisting in mineral homeostases. In young adults, bone remodelling is usually balanced with approximately as much bone replaced as is removed during each remodelling cycle. However, when remodelling becomes accelerated in combination with an imbalance that favours bone resorption over formation, such as during menopause, precipitous losses in bone mass occur. Bone turnover markers (BTMs) measure the rate of bone remodelling allowing for a dynamic assessment of skeletal status and hold promise in identifying those at highest risk of rapid bone loss and subsequent fracture. Further, the use of BTMs to monitor individuals administered osteoporosis therapy is attractive as monitoring anti-fracture efficacy with bone mineral density has significant limitations. This review details remodelling biology, pre-analytical and analytical sources of variability for BTMs, describes the most commonly used resorption and formation markers, and offers some guidelines for their use and interpretation in the laboratory and the clinic.

Introduction

In the assessment of risk for fragility fracture and in the management of postmenopausal osteoporosis (PMO), bone mineral density (BMD) assessed by dual-energy X-ray absorptiometry (DXA) is the most commonly used measure. BMD by DXA provides a static measure of skeletal status: a snapshot of the cumulative effects of different factors on the assessed skeletal site up until the time of measurement. What DXA BMD does not provide is a dynamic estimate of skeletal activity which could provide insight into the changes the skeleton may undergo in the future.

BMD by DXA is only one of a number of factors that quantify fracture risk [1], [2]. Bone turnover markers (BTMs) are emerging as promising tools in the management of PMO as they provide dynamic information regarding skeletal status that is independent from, and often complementary to, BMD measurements [3]. In the past, BTMs were primarily reserved for research; however, with recent refinements in methodology and with clinical data linking BTMs to fracture risk [4], [5], [6], [7], [8], the use of BTMs is increasing in clinical practice.

Section snippets

Remodelling biology

Bone is a remarkable structure being stiff yet flexible, strong but light, with most bones' anatomical structure largely determined by the loads they repeatedly bear. In recent years, the physiology of bone and the cells and metabolic pathways involved and their intricate interactions have become better understood.

All materials subjected to repeated cyclical loading suffer stress fatigue and the skeleton is no exception; necessarily, bone is a dynamic tissue that is continually renewed through

General pre-analytical variability with bone turnover markers

Perhaps the greatest challenge for the adoption of BTMs within the clinical setting is their potentially high variability. It is essential to understand sources of pre-analytical and analytical variability and to employ strategies to minimize these factors to maximize the signal-to-noise ratio for enhanced diagnostic utility.

A variety of pre-analytical factors influence BTM concentrations, and thus their variability when measured, including: food intake, growth, sex, seasonal changes, circadian

General analytical methods and variability

Specific commercial BTM assays such as serum C-telopeptide (CTX) and urine N-telopeptide (NTX) are available for assessment of bone resorption, whereas serum bone-specific alkaline phosphatase (BALP), serum osteocalcin, or serum procollagen type 1 N-terminal propeptide (PINP) are available for assessment of bone formation. In general, automated assays are more precise and cost-effective, and therefore, preferable for routine laboratory testing [33], [34].

Table 1 lists assays commercially

Reporting bone turnover marker values

Traditionally most laboratory results are reported with a reference interval. The use of reference intervals with BTMs are limited as BTMs consistently demonstrate large degrees of variability between individuals and between age and physiological maturity [22], [59], [61], [62], [63], [64], [65]. These intervals are even wider in the postmenopausal group which limits the use of a normal reference interval in the interpretation of BTMs in this population.

Most clinical practice guidelines have

Introduction to biochemical markers of bone turnover

BTMs are valuable for assessing the dynamic nature of bone. When paired with static BMD data, BTMs may enhance the estimation of the future risk of fracture and may independently provide a valuable tool for the monitoring of therapy [8]. BTMs are measured in the urine or serum, with urinary samples requiring correction for creatinine, adding an additional step to most procedures.

During the remodelling cycle, active cells synthesize proteins or release degradation products which can be measured

Osteocalcin analyte

Osteocalcin, the most abundant non-collagenous protein found in bone [77], is a 49-amino acid peptide containing up to three gamma-carboxyglutamic acid residues which are responsible for the calcium-binding properties of the molecule [78]. During osteoid synthesis osteocalcin is released by osteoblasts. The precise function of osteocalcin is not known, but it is likely involved in influencing osteoid mineralization and providing negative feedback during the bone remodelling process. Newly

N-telopeptide analyte

Of the many collagen degradation fragments measured, assay of the N-telopeptide fragment (Fig. 1) in urine (uNTX) has been one of the most widely used in clinical practice, at least until recently. Available commercially in ELISA format (Table 1), the assay relies on a purified antigen for calibration, and a matching creatinine concentration for normalization. An automated ELISA assay is also available (Table 1), and appears to correlate very well (r = 0.977) with the manual one, but this has not

Other bone turnover markers

A number of BTMs are not discussed in this document. For example, previously total urinary hydroxyproline and total ALP activity or ALP fractionation were the standards of the time. To a large extent, urinary hydroxyproline has fallen into disfavour as a marker of bone resorption because it is a complex and expensive manual assay with poor performance characteristics, it is not specific for bone, and it is significantly affected by food intake [114]. On the other hand, total ALP can still be

Diagnosis of postmenopausal osteoporosis

While population studies consistently report increased levels of BTMs in groups of women with PMO [9], [115] and inverse relationships between BMD and BTM concentrations, particularly in the elderly [116], [117], BTMs cannot be used to diagnose PMO in an individual [8], [70], [118].

Prediction of bone loss in untreated postmenopausal women

In untreated postmenopausal women, the possible relationship between changes in BMD and BTM levels is limited by the lassitude of BMD measurements, the variations of bone loss over time and, depending on skeletal

Impact on the lab

The implementation of new BTM assays may have a role as part of the clinical evaluation of PMO and in monitoring therapy as discussed in this paper. However, availability of these assays will have a significant impact on laboratory resources. If made widely available, BTM assays are likely to generate a significant analytical volume in laboratories. Each laboratory will need to choose appropriate BTMs taking into consideration clinical preferences, availability of methodology and overall cost.

Summary

Despite their relatively high variability, both pre-analytically and analytically, the differences in BTMs between those with normal (premenopausal) and elevated (osteoporosis) turnover are generally greater. This characteristic allows for the use of BTMs to identify those persons at high risk for bone loss and subsequent fracture. Further, the use of BTMs to monitor the efficacy of osteoporosis therapies holds promise. Decreasing controllable variability is crucial, from both the analytical

Endorsements

These recommendations were reviewed and endorsed by the following organizations:

  • Association des Biochimistes Cliniques du Québec

  • Association des Médecins Biochimistes du Québec

  • Canadian Association of Medical Biochemists

  • Canadian Society of Clinical Chemists

  • Canadian Panel of the International Society for Clinical Densitometry

  • Canadian Society for Endocrinology and Metabolism

  • Society of Obstetricians and Gynaecologists of Canada

Acknowledgments

We gratefully acknowledge the contributions of Elke Henneberg. These recommendations were developed by a multidisciplinary working group under the auspices of the Scientific Advisory Council of Osteoporosis Canada.

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    This project was a result of an unrestricted grant from Osteoporosis Canada. The funding source had no role in the development of these recommendations.

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