ReviewBone turnover markers in the management of postmenopausal osteoporosis☆
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.
References (137)
- et al.
Serum type I collagen breakdown product (serum CTX) predicts hip fracture risk in elderly women: the EPIDOS study
Bone
(2000) - et al.
Age- and sex-related changes in iliac cortical bone mass and remodeling
Bone
(1993) - et al.
Bone remodelling: its local regulation and the emergence of bone fragility
Best Pract. Res. Clin. Endocrinol. Metab.
(2008) - et al.
Osteocyte morphology in fibula and calvaria — is there a role for mechanosensing?
Bone
(2008) - et al.
Vitamin D status in postmenopausal women living at higher latitudes in the UK in relation to bone health, overweight, sunlight exposure and dietary vitamin D
Bone
(2008) - et al.
The stability of pyridinium crosslinks in urine and serum
Clin. Chim. Acta
(1995) - et al.
Establishing a reference range for bone turnover markers in young, healthy women
Bone
(2008) - et al.
A cross-sectional study of bone turnover markers in healthy premenopausal women
Bone
(2007) - et al.
The amino- and carboxyterminal cross-linked telopeptides of collagen type I, NTX-I and CTX-I: A comparative review
Clin. Chim. Acta
(2008) - et al.
Comparison of the analytical and clinical performance characteristics of an N-MID versus an intact osteocalcin immunoradiometric assay
Clin. Chim. Acta
(2000)
Pediatric reference intervals for bone markers
Clin. Biochem.
Response rate of bone mineral density to teriparatide in postmenopausal women with osteoporosis
Bone
Serum bone Gla-protein compared to bone histomorphometry in endocrine diseases
Bone
Degradation of bone matrix proteins by osteoclast cathepsins
Int. J. Biochem.
Reduction in PINP, a marker of bone metabolism, with raloxifene treatment and its relationship with vertebral fracture risk
Bone
Effect of feeding on bone turnover markers and its impact on biological variability of measurements
Bone
2002 Clinical practice guidelines for the diagnosis and management of osteoporosis in Canada
CMAJ
Case finding for the management of osteoporosis with FRAX—assessment and intervention thresholds for the UK
Osteoporos. Int.
Biochemical indices of bone turnover and the assessment of fracture probability
Osteoporos. Int.
Identification of osteopenic women at high risk of fracture: the OFELY study
J. Bone Miner. Res.
Markers of bone resorption predict hip fracture in elderly women: the EPIDOS Prospective Study
J. Bone Miner. Res.
Serum bone alkaline phosphatase and calcaneus bone density predict fractures: a prospective study
Osteoporos. Int.
Biomarkers for osteoporosis management: utility in diagnosis, fracture risk prediction and therapy monitoring
Mol. Diagn. Ther.
Increased bone turnover in late postmenopausal women is a major determinant of osteoporosis
J. Bone Miner. Res.
The degree of mineralization of bone tissue measured by computerized quantitative contact microradiography
Calcif. Tissue Int.
Control of bone mass and remodeling by PTH receptor signaling in osteocytes
PLoS ONE
Diurnal rhythm of CrossLaps in human serum
Clin. Chem.
Application of a new serum assay for type I collagen cross-linked N-telopeptides: assessment of diurnal changes in bone turnover with and without alendronate treatment
Calcif. Tissue Int.
Bone turnover marker profile in relation to the menstrual cycle of premenopausal healthy women
Menopause
Seasonal changes in vitamin D status and bone turnover in healthy Irish postmenopausal women
Int. J. Vitam. Nutr. Res.
Supplementation with oral vitamin D3 and calcium during winter prevents seasonal bone loss: a randomized controlled open-label prospective trial
J. Bone Miner. Res.
Biochemical markers of bone turnover and the volume and the density of bone in children at different stages of sexual development
J. Bone Miner. Res.
Biochemical markers of bone turnover in girls during puberty
Clin. Endocrinol. (Oxf)
Effects of age and estrogen status on serum parathyroid hormone levels and biochemical markers of bone turnover in women: a population-based study
J. Clin. Endocrinol. Metab.
Clearance of osteocalcin by peritoneal dialysis in children with end-stage renal disease
Pediatr. Res.
Serum immunoreactive bone sialoprotein as a new marker of bone turnover in metabolic and malignant bone disease
J. Clin. Endocrinol. Metab.
The effects of brisk walking on markers of bone and calcium metabolism in postmenopausal women
Calcif. Tissue Int.
Changes in bone turnover induced by aerobic and anaerobic exercise in young males
J. Bone Miner. Res.
The effects of twelve weeks of bed rest on bone histology, biochemical markers of bone turnover, and calcium homeostasis in eleven normal subjects
J. Bone Miner. Res.
Changes in bone mass and bone turnover following distal forearm fracture
Osteoporos. Int.
Determination of pyridinoline and deoxypyridinoline in urine, with special attention to retaining their stability
Clin. Chem.
Effect of different storage temperatures, sample collection procedures and immunoassay methods on osteocalcin measurement
Eur. J. Clin. Chem. Clin. Biochem.
Evaluation of a fully automated serum assay for C-terminal cross-linking telopeptide of type I collagen in osteoporosis
Clin. Chem.
Automated and manual assays for urinary crosslinks of collagen: which assay to use?
Exp. Clin. Endocrinol. Diabetes
Current databases on biological variation: pros, cons and progress
Scand. J. Clin. Lab. Invest.
Response of biochemical markers of bone turnover to hormone replacement therapy: impact of biological variability
J. Bone Miner. Res.
Intra-individual variation in serum type I procollagen carboxy-terminal propeptide and type I collagen carboxy-terminal cross-linked telopeptide concentrations
Ann. Clin. Biochem.
Clinical evaluation of the Serum CrossLaps One Step ELISA, a new assay measuring the serum concentration of bone-derived degradation products of type I collagen C-telopeptides
Clin. Chem.
Clinical evaluation of the Elecsys beta-CrossLaps serum assay, a new assay for degradation products of type I collagen C-tlopeptides
Clin. Chem.
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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.