Clinical Utility of Biochemical Markers
of Bone Turnover

Osteoporosis is a disease characterized by reduced bone mass, deterioration of bone architecture, and increased bone fragility that leads to increased risk of fractures of the spine, hip and wrist. It afflicts approximately 10 million Americans, 80 percent of them women, with annual related healthcare costs in the US estimated at $14 billion. Assays for markers of bone metabolism may have an important potential role to play in the detection of individuals at risk for high bone resorption and in the monitoring of patients undergoing treatment.

Bone metabolism
Bone is a metabolically active and dynamic tissue that undergoes constant remodeling or "turnover." Bone remodeling is characterized by two processes mediated by two kinds of bone cells: bone resorption, in which osteoclasts degrade "old" bone; and bone formation, in which osteoblasts fill the resorption cavities with "new" bone. Bone turnover occurs in anatomically distinct foci called bone remodeling units. The resorption phase requires a 1- to 3-week period.¹ The formation phase requires 8 to 12 weeks to refill the cavity. In a healthy adult, bone resorption and formation are tightly coupled within a bone remodeling unit. Figure 1 illustrates the bone remodeling process.

For an enlarged view, click on the image.

Figure 1. The cycle of bone remodeling starts with bone resorption and is followed by bone formation. (Adapted from de Vernejoul.⁹)

Bone mass depends on two factors: 1) the coupling of bone resorption and formation in a remodeling unit, and 2) the number of remodeling units activated in a given area of bone.¹ Bone loss results from an imbalance or uncoupling of the resorption and formation phases within a given bone remodeling unit, and by a significant increase in the activation frequency of these remodeling units.² It is via this latter mechanism that the increased bone turnover and bone loss associated with estrogen deficiency and menopause occur.² In fact, the estrogen deficiency associated with menopause is the most common cause of osteoporosis. Figure 2 shows the remodeling imbalance in trabecular bone. Other causes of bone loss include endocrine disorders, certain medications, certain lifestyle behaviors and skeletal complications of malignancies.

For an enlarged view, click on the image.

Figure 2. Two mechanisms for imbalance in trabecular bone remodeling. The upper row represents the balance present in healthy young adults, in which osteoblasts replace bone in the resorption cavity produced by osteoclasts. The middle row displays osteoblast-mediated bone loss, in which a resorption cavity of normal depth is filled by osteoblasts with an insufficient amount of new bone. The lower row displays osteoclast-mediated bone loss, in which the normal amount of new bone does not totally compensate for the excessive resorption by osteoclasts. (Adapted from Parfitt AM.¹⁰)

Markers of bone turnover
The biochemical actions of osteoclasts or osteoblasts during bone remodeling can be assessed by measuring their enzymatic activity, or by measuring bone matrix components released into the circulation.³ During bone resorption, breakdown products, such as deoxypyridinoline (Dpd) and the N-terminal telopeptide (NTX) from the type I collagen digested by osteoclasts, are released into the bloodstream and excreted unmetabolized in urine.³ Bone formation markers are released into the circulation during the synthesis of new bone protein matrix and include bone-specific alkaline phosphatase (BSAP) and osteocalcin (bone gla protein). Measurements of these products are indicative of the rate of bone turnover.³ Tests for several biochemical markers of bone metabolism are currently available for use in the research and clinical settings. Bone formation markers are typically measured in serum, whereas markers of bone resorption are typically measured in urine. Recently, however, tests for measuring bone resorption markers in serum have also become available. The urinary markers of bone resorption are derived from type I collagen. Although pyridinoline (Pyr) is found in type I collagen, it is also found in type II collagen of cartilage. Table 1 lists each marker, its tissue of origin and its tissue specificity.⁴

Table 1. Biochemical markers of bone turnover.

Bone formation markers are released into the circulation during the synthesis of new bone protein matrix. BSAP, unlike total alkaline phosphatase, is a product of osteoblastic activity and is highly specific to bone.^2,4 Serum osteocalcin is a sensitive marker of osteoblastic activity since osteocalcin is a noncollagen protein found only in bone and dentin.

Clinical utility of markers of bone turnover
Much discussion has focused on the clinical utility of these biochemical markers of bone turnover. Since bone mass accounts for up to 80 percent of the variance in bone strength, a low bone mineral density (BMD) is currently the single most important risk factor for osteoporosis and fracture. Moreover, BMD has been reported as a better predictor of fracture risk than cholesterol is for coronary heart disease or than blood pressure is for stroke.⁵ Thus, biochemical markers of bone turnover have a potential role in clinical patient management when used in conjunction with BMD assessments. Biochemical markers of bone turnover are not advocated as a means to diagnose osteoporosis. Rather, they may represent an improved parameter for monitoring the response to antiresorptive therapy because they can show the early effects of interventions (within 1 to 3 months), far in advance of the long-term effects observed with BMD, which requires at least 12 to 18 months before a change is measurable.^2,4 The effectiveness of antiresorptive therapy in slowing or halting bone loss can be recognized by a return to normal values. In fact, changes in the urinary markers of bone resorption can be seen as soon as one month following estrogen replacement or alendronate therapy.^6,7 Biochemical markers of bone turnover also present a means to monitor, in an objective manner, compliance with therapy. Showing the reluctant patient the changes effected in a short time may also help to maintain long-term compliance.

Should osteoporosis risk factors and the initial clinical assessment indicate a patient's high risk for bone loss, bone turnover measurements can be helpful for identifying women with significantly increased bone turnover, particularly bone resorption, even in the face of a normal BMD. The rate of bone loss in the axial skeleton increases two- to fourfold after the menopausal transition and is accompanied by increased bone turnover. The clinical challenge then is to monitor and document therapeutic interventions to slow bone loss. A more desirable scenario would be to prevent osteoporosis in women at risk for bone loss prior to any significant reduction in bone mass. Many women at the time of menopause present with normal bone mass but increased bone resorption. The immediate menopausal transition represents a period of high volatility for bone health in which rapid bone loss is realized if an antiresorptive therapy is not initiated. Longitudinal BMD measurements are ineffective in the short-term assessment of changes in bone status. Short-term monitoring of bone markers presents an opportunity to document response to therapy, may encourage the patient to stay with therapy, and also affords early opportunities to monitor compliance--a well-documented problem with hormone-replacement regimens.

Table 2. Causes of abnormal bone turnover.

Variability in measurement
Although biochemical bone markers have improved the information available to clinicians when managing patients, caution must be taken when interpreting baseline results and multiple assessments across time while monitoring therapy. Inherent variability is associated with each bone marker assessment and false conclusions may be drawn from a single value if the variability is high. Thus, to assess accurately whether a patient is a candidate for antiresorptive therapy or whether such therapy is effective requires a knowledge of the variability associated with each marker used.

Two types of variability are associated with bone marker measurements: analytical variability and biological variability.⁸ Analytical variability is related to the performance characteristics of a given assay; these are a function of the analyte itself, combined with the design and quality of the assay methodology. Biological variability includes variability for a single patient over a single day, for a single patient from day to day, and from person to person within a given population.⁸ A good biochemical marker of bone metabolism will have not only minimal analytical variability, but also minimal biological variability. Nonetheless, every effort should be made to minimize variability by taking at least two baseline measurements, then collecting follow-up samples at the same time of day as that of the baseline measurements. Analytical and biological variability must be kept to a minimum to obtain clinically relevant results.

Conclusion
Biochemical markers of bone metabolism offer several potential advantages:

• the short-term assessment of response to antiresorptive therapy
• an objective short-term measure of compliance with therapeutic intervention
• (in combination with BMD) a better and more thorough risk assessment for potential bone loss than is possible using BMD alone
• a dynamic measure of bone compared to the static measure provided by BMD, so that women can be identified at the menopause as having high resorption and treated before rather than after bone is lost.⁴

The assessment of bone turnover has received much attention over the past few years because of the need for a sensitive marker for the early identification of osteoporosis in the clinical setting. Combining the use of BMD measurements and bone marker assessments may offer a means to monitor the short-term response to therapy and improve patient compliance to a therapeutic regimen. Much research is under way to improve assay variability and specificity which will likely improve the clinical utility of these assays.

References

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2. Delmas, PD. Biochemical markers for the assessment of bone turnover. In: Riggs BL, Melton LJ, editors. Osteoporosis: etiology, diagnosis and management. 2nd ed. Philadelphia: Lippencott-Raven Publishers, 1995.

3. Delmas PD. Biochemical markers of bone turnover. I: Theoretical considerations and clinical use in osteoporosis. Am J Med 1993;95:11S-16S.

4. Seibel MJ, Baylink DJ, Farley JR, Epstein S, Yamauchi M, Eastell R, et al. Basic science and clinical utility of biochemical markers of bone turnover--a Congress report. Exp Clin Endocrinol Diabetes 1997;105:125-33.

5. Marshall D, Johnell O, Wedel H. Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. BMJ 1996;312:1254-9.

6. Prestwood KM, Kenny AM, Robbins B, et al. Low dose estrogen reduces bone resorption in older women: a randomized, double blind, placebo-controlled study. J Am Geriatr Soc 1998;46:S10.

7. Bettica P, Bevilacqua M, Vago T, Masino M, Cucinotta E, Norbiato G. Short-term variations in bone remodeling biochemical markers: cyclical etidronate and alendronate effects compared. J Clin Endocrinol Metab 1997;82:3034-9.

8. Ju HS, Leung S, Brown B, Stringer MA, Leigh S, Scherrer C, et al. Comparison of analytical performance and biological variability of three bone resorption assays. Clin Chem 1997;43:1570-6.

9. de Vernejoul M-C. Bone structure and function. In: Geusens P, editor. Osteoporosis in clinical practice: a practical guide for diagnosis and treatment. New York: Springer-Verlag, 1998: 3.

10. Parfitt AM. Bone remodeling: relationship to the amount and structure of bone, and the pathogenesis and prevention of fractures. In: Rigg BL, Melton LJ III, editors. Osteoporosis: etiology, diagnosis, and management. New York: Raven Press, 1988: 45-94.