You are in: eMedicine Specialties > Endocrinology > Metabolic Bone Disease Utility of Bone Markers in OsteoporosisArticle Last Updated: Oct 8, 2007AUTHOR AND EDITOR INFORMATIONSection 1 of 10
 
Author: Sonia A Talwar, MD, Assistant Professor of Medicine, State University of New York at Stony Brook, Associate Director, Bone Mineral Research Center, Division of Endocrinology, Winthrop-University Hospital Sonia A Talwar is a member of the following medical societies: American Society for Bone and Mineral Research Coauthor(s): John F Aloia, MD, Chief Academic Officer, Associate Dean, Professor, Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, State University of New York at Stony Brook School of Medicine Editors: Steven R Gambert, MD, Program Director, Physician-in-Chief, Professor, Department of Internal Medicine, Sinai Hospital, Johns Hopkins University School of Medicine; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; George T Griffing, MD, Professor of Medicine, Director of General Internal Medicine, St Louis University Author and Editor Disclosure Synonyms and related keywords: bone turnover markers, bone metabolism, bone loss, bone resorption, bone mineral density, BMD, bone formation markers, bone resorption markers, osteoporosis, fracture risk, bone loss INTRODUCTIONSection 2 of 10
 
The field of bone turnover markers has developed considerably in the past decade. Biochemical monitoring of bone metabolism depends upon measurement of enzymes and proteins released during bone formation and of degradation products produced during bone resorption. Various biochemical markers are now available that allow a specific and sensitive assessment of the rate of bone formation and bone resorption of the skeleton. Although these markers are not recommended for use in diagnosis of osteoporosis yet, they appear to be useful for the individual monitoring of osteoporotic patients treated with antiresorptive agents. A summary list of bone formation markers is as follows:
A summary list of bone resorption markers is as follows:
Such markers can also be useful in selected cases to improve the assessment of individual fracture risk when bone mineral density (BMD) measurement by itself does not provide a clear answer. The combined use of BMD measurement and bone markers is likely to improve the assessment of the risk of fractures in those cases. BONE FORMATION MARKERSSection 3 of 10
Serum total alkaline phosphatase and bone-specific alkaline phosphatase Alkaline phosphatase has been clinically available for several years as a marker for bone metabolism. Serum alkaline phosphatase consists of several dimeric isoforms that originate from various tissues like liver, bone, intestine, spleen, kidney, and placenta. In adults with normal liver function, approximately 50% of the total alkaline phosphatase activity arises from the liver and 50% arises from the bone. The recent development of immunoassay-based markers with monoclonal antibodies directed to the bone-specific isoform of alkaline phosphatase has improved both specificity and sensitivity. Changes in bone-specific alkaline phosphatase can lag by several weeks. Following the start of antiresorptive therapy, the suppression is observed with the resorption markers as the coupling process is normalized. Serum osteocalcin Osteocalcin is a small protein (49 amino acids) synthesized by mature osteoblasts, odontoblasts, and hypertrophic chondrocytes. Serum osteocalcin is considered a specific marker of osteoblast function, as its levels correlate with the bone formation rate. However, the peptide is rapidly degraded in the serum, and both intact and fragmented segments coexist in the serum. The resulting heterogeneity of the osteocalcin fragments in the serum leads to limitations with the use of this marker. Osteocalcin levels follow a circadian rhythm characterized by a decline during the morning, a low around noon, and a gradual increase to a peak after midnight. Serum osteocalcin levels reportedly vary significantly during the menstrual cycle, with the highest levels observed during the luteal phase. The major advantages to using osteocalcin as a clinical index of bone turnover are its tissue specificity, its wide availability, and its relatively low within-person variation. In general, serum levels are elevated in patients with diseases characterized by a high bone turnover rate, and the serum levels reflect the expected changes in bone formation following surgical and therapeutic intervention. An exception is found in Paget disease, in which serum alkaline phosphatase is a better predictor of severity of disease than osteocalcin. Procollagen type 1 propeptides derived from newly formed type 1 collagen Procollagen type 1 contains N- and C-terminal extensions, which are removed by specific proteases during conversion of procollagen to collagen. The extensions are the C- and N-terminal propeptides of procollagen type 1 (P1CP and P1NP). Anti-P1NP antibodies are used to detect the trimeric structure of P1NP by enzyme-linked immunosorbent assay (ELISA) or radioimmunoassay. Measurement of P1NP appears to be a more sensitive marker of bone formation rate in osteoporosis. These assays are being developed for clinical use. BONE RESORPTION MARKERSSection 4 of 10
The most useful markers of bone resorption are degradation products derived from the enzymatic hydrolysis of type 1 collagen, particularly peptides related to regions of cross-linking with PYD. Collagen type 1 represents over 90% of the protein in bone, and it is natural that many bone markers are derived from released collagen fragments. Advances have been made in utilizing noncollagenous proteins and enzymes for serum assays of bone resorption. Their application is becoming increasingly widespread. Collagen-derived assays Until the early 1990s, urinary hydroxyproline was one of the main bone resorption markers available, but this assay lacked specificity and sensitivity. Hydroxyproline is a component of the bone collagen. During degradation of bone, it is released into the serum and reaches the urine in free and bound forms. Today, serum hydroxyproline is considered a nonspecific marker of bone turnover since it is derived from the degradation of newly synthesized collagens, from collagens of tissues other than bone, and from diet as well. Therefore, more specific techniques have replaced urinary hydroxyproline. From a practical standpoint, another major drawback of urinary hydroxyproline was the necessity for dietary restrictions on gelatin intake before applying the test. Cross-link assays Hydroxypyridinium cross-links of collagen, PYD, and DPD (see Image 1). The pyridinium compounds, PYD and DPD, are formed during the extracellular maturation of fibrillar collagens and are released upon the degradation of mature collagens. The measurement of PYD and DPD is not influenced by degradation of newly synthesized collagens and independent of dietary sources. While PYD is found in cartilage, bone, ligaments, and vessels, DPD is found in bone and dentin only. The PYD/DPD ratio in urine is similar to the ratio of these two cross-links in bone, which suggests that both of the cross-links are derived predominantly from bone. Both PYD and DPD are present in urine as free moieties (40%) or peptide bound (60%). Free forms can be detected by direct immunoassays (free DPD, Pyrilinks-D). Peptide assays Rather than use the cross-links themselves as markers, several groups have developed assays based on specific antibodies raised against isolated collagen peptides containing cross-links. These fragments detected by radioimmunoassay technique are available for C-telopeptide of type 1 collagen (CTX, CrossLaps) and cross-linked N-terminal telopeptide of type 1 collagen by ELISA technique (NTX, Osteomark). The monoclonal antibody used for NTX assay is directed against the urinary pool of collagen cross-links derived from a patient with Paget disease. Only β-isomer of CTX is measured in serum CrossLaps assay, while both α- and β-isomers of CTX are measured in urine CrossLaps assay. These assays showed detectable reaction with urine from healthy individuals as well as largeincreases associated with elevated turnover. Currently, 2 categories of C-telopeptide methods exist: the CTX and type I collagen cross-linked C-telopeptide (ICTP). These recognize different segment domains of C-terminal telopeptide region of the α1 chain of type 1 collagen and respond differently to bone metabolic processes. While CTX responds remarkably to antiresorptive therapies, serum ICTP is insensitive to normal metabolic bone processes, such as osteoporosis, but serum ICTP may be a marker of bone degradation in pathological conditions (eg, bone metastasis, rheumatoid arthritis). The pyridinium cross-links and the collagen telopeptides involving the cross-linking sites are considered the best indices for the assessment of bone resorption. Circadian rhythm in bone metabolism causes markers to vary by 10-20%. Urine creatinine varies during the day by 20%. Urine cross-links/creatinine ratios vary by 20-30%. This variability could be corrected by measuring the markers in the morning (first or second void urine) when the levels are the highest. Serum CTX is the mostly commonly used measurement since it has been automated and there is a large amount of data available supporting the use of urine and serum CTX for following antiresorptive therapy. Noncollagenous markers Relatively few noncollagenous proteins or glycoproteins have sufficient specificity for bone to be considered potential markers. BSP is thought to be involved in the mineralization of newly deposited bone matrix and/or the calcification of extraskeletal tissues. BSP is a highly acidic protein with strong affinity for hydroxylapatite crystals. BSP may be a sensitive marker of bone turnover, and clinical data obtained so far suggest its serum levels predominantly reflect processes related to bone resorption. The discovery that the type 5b isotype is specific for bone osteoclasts has facilitated an antibody capture activity assay for tartrate-resistant acid phosphatase 5b as a bone resorption marker but is still under development. USE OF BONE MARKERS IN DIAGNOSIS OF OSTEOPOROSISSection 5 of 10
Diagnosis of osteoporosis is not based on evaluation of bone markers, and BMD assessment is still the criterion standard for evaluation and diagnosis. However, mean values for markers of bone turnover are higher in osteoporosis patients than in the matched controls. In various studies, the mean urinary excretion of DPD is 20-100% higher in patients with osteoporosis than in healthy subjects. In another study, an inverse relationship between the quartile of urinary NTX excretion and mean BMD exists, but these results are not consistent. Moreover, values of healthy subjects and patients with osteoporosis overlap substantially. Therefore, measurement of bone markers is not recommended to make a diagnosis of osteoporosis. USE OF BONE MARKERS IN PREDICTING FUTURE RISK OF BONE LOSSSection 6 of 10
BMD is an important predictor of fracture risk; however, a single measurement indicates only current BMD, not the anticipated rate of bone loss. Patients with a given BMD who are losing bone rapidly have a greater risk of fracture later in life. Nonetheless, patients with low BMD or high marker values would be at risk for osteoporosis and warrant preventive measures with antiresorptive agents. Relationship between biochemical markers of the bone turnover and the rate of bone loss has been investigated in prospective studies that show conflicting results because of the various technical limitations, like precision error of the repeated measurements of bone markers and precision error of BMD measurements for rate of bone loss. Analysis of studies investigating whether baseline turnover markers can predict the bone density changes in patients treated with antiresorptive drugs has been controversial. In a subset analysis of a trial with alendronate, the baseline NTX or other parameters did not correlate with subsequent spine or hip BMD.2 The correlation was weak between baseline NTX and the change in spine BMD after 2 years of 2.5 mg alendronate. Baseline markers of bone turnover provide insight into the state of the remodeling units in the adult skeleton. In both younger and older postmenopausal women, resorption and the formation markers do predict, with some degree of confidence, the degree of bone loss without therapeutic intervention. However, the data published suggest that baseline turnover markers do not predict the response to therapy. ASSESSMENT OF FRACTURE RISK FROM BONE MINERAL DENSITY AND BONE TURNOVER MARKERSSection 7 of 10
The level of bone mass can be assessed with adequate precision by measuring BMD using dual-energy x-ray absorptiometry (DEXA). However, this measurement does not capture all risk factors for fracture. Bone fragility also depends on the morphology, the architecture, and the remodeling of bone, as well as on the quality (properties) of the bone matrix that cannot be readily assessed. In addition, the risk of fracture is also influenced by muscle function, the propensity to fall, and the ability to adapt to such falls. With emergence of effective but rather expensive treatments, detecting those women at higher risk of fracture is essential. Several prospective studies have demonstrated a strong association between BMD and the risk of hip, spine, and forearm fractures. However, half of the patients with incident hip fractures have baseline BMD assessed by DXA above the diagnostic threshold of osteoporosis, defined as a T-score of -2.5 SD or more. Clearly, improvement is needed in the identification of patients at risk for fracture. In the large cohort of elderly women in France (EPIDOS), no significant relationship was found between levels of serum osteocalcin and bone alkaline phosphatase and the risk of hip fracture occurring during a 2-year follow-up. In contrast, two prospective studies in younger healthy postmenopausal women (OFELY and HOS) showed a significant positive association between an increased level of bone alkaline phosphatase and the risk of vertebral and nonvertebral fracture was observed. Born resorption assessed based on urinary and serum CTX or urinary free DPD above the normal premenopausal range were consistently associated with about 2-fold higher risk of hip, vertebral, and other fractures over follow-up periods ranging from 1.8-5 years. The combination of BMD and bone turnover measurement allows the identification of women at a much higher risk for hip fracture. The potential validity of this approach can be illustrated by the following results: Fracture Risk Based on BMD and Biochemical Bone Turnover Markers*
*Adapted from Garnero p, Hausherr E, Chapuy MC. Markers of bone resorption predict hip fracture in elderly women, the EPIDOS Prospective Study. J Bone Miner Res 1996 Oct; 11(10): 1531-8.3 The following recommendations for preventive therapy have been proposed based on the above findings:
Finally, a global diagnostic approach is desirable because the pathogenesis of fragility fractures is multifactorial, including not only the level of BMD but also bone architecture and bone matrix quality, bone turnover, fall-related factors, and muscle function. The combination of diagnostic tests should be validated in prospective studies. In addition, the value of bone turnover markers to predict fracture risk should be explored in large and long-term studies in other populations such as men, other ethnic groups, and people on steroids. The following guidelines apply to the use of bone markers in prediction of fragility fractures:
USE OF BONE MARKERS IN MONITORING TREATMENT OF OSTEOPOROSISSection 8 of 10
The goal of treatment is to reduce the occurrence of fragility fractures, but their incidence is low, and the absence of events during the first years of therapy does not necessarily imply that treatment is effective. BMD assessment with DEXA is a surrogate marker of treatment efficacy that has been widely used in clinical trials. Given short-term precision error of 1-1.5% of BMD measurement at the spine and hip, the individual change must be greater than 3-5% to be significant. With potent bisphosphonates such as alendronate and risedronate, repeating BMD measurement 2 years after initiating therapy will show whether a patient is responding to therapy. Patients who are responding to therapy have a significant increase in BMD at least at the lumbar spine, which is the most responsive site. With treatments such as raloxifene or nasal calcitonin that induce much smaller increases in BMD, DEXA is not appropriate to monitor therapy. With any treatment, DEXA may not reveal all responders within the first year of therapy. This relatively low signal-to-noise ratio of this technique does not allow rapid (within months) differentiation of responders from nonresponders. Baseline bone turnover markers are weak predictors of the response to therapy with antiresorptive drugs; however, the change in bone markers is of greater value. Some women continue to lose bone while receiving antiresorptive therapy. This has been estimated to occur in approximately one third of women receiving estrogen and one sixth of those receiving bisphosphonates. Failure to respond may be due to noncompliance, poor intestinal absorption of drug, other factors contributing to bone loss, or other unidentified factors. Monitoring treatment of osteoporosis with bone markers may have the added advantage of improving compliance. Most of the effective antiresorptive treatments induce a decrease in bone turnover that reaches a plateau within a few weeks or months, depending on the potency and route of administration of the drug and on the marker. Thus, individual patients can be monitored with bone markers earlier than with DEXA. A recent study indicates that monitoring bisphosphonate therapy with bone marker measurement at baseline, 3, and 6 months can improve the compliance to therapy by 20% at 1 year. A decrease greater than 50% and 30% in urinary NTX and serum CTX respectively provides evidence of compliance and drug efficacy. Therefore, monitoring with bone markers during treatment is recommended. For a 90% specificity to predict a positive BMD response (+3%), cut-offs, expressed as a percentage decrease from baseline, are as follows:
On average a change of greater than 30% is significant. In case of an equivocal change in bone markers, a third measurement should be taken 3 months later. Recommendations for the use of bone markers in monitoring antiresorptive therapy in postmenopausal women with osteoporosis can be summarized as follows:
MULTIMEDIASection 9 of 10
REFERENCESSection 10 of 10
Utility of Bone Markers in Osteoporosis excerpt Article Last Updated: Oct 8, 2007 | |||||||||||||||||||||||||||||||||||||||||||||||||
