Serum and Urine Bone Markers in the Management of Osteoporosis

Abstract and Introduction

Abstract

Osteoporosis is a common disease characterized by decreased bone mass, increased bone turnover, and increased susceptibility to fracture. Almost 44 million Americans are estimated to have low bone mass, which puts them at increased risk of developing osteoporosis and fractures. Osteoporosis is diagnosed by a low bone density (BMD) measurement, because a low BMD is known to contribute to increased fracture risk, which is the main source of morbidity and mortality for osteoporosis. However, changes in bone mass and density in response to anti-resorptive therapy account for only a small portion of the predicted fracture risk reduction. Whereas dynamic changes in bone turnover, estimated by measurement of bone biochemical markers, such as breakdown products of type-I collagen and proteins secreted by osteoblasts and osteoclasts in blood and urine, can account for a major portion of anti-fracture efficacy of anti-resorptive agents. Most anti-resorptive agents act by rapidly reducing bone markers. This has led to advocacy for use of bone turnover markers, in complement to BMD measurement, in the management of osteoporosis. In general, higher bone turnover is associated with accelerated bone loss and potential deterioration in bone quality. Several clinical trials have established the potential utility of markers to identify patients with rapid bone loss, to aid in therapeutic decision-making, and to monitor therapeutic efficacy of various treatments. Elevated marker levels have been shown to be associated with increased risk of fracture in elderly women, but their utility in predicting fracture is not yet established. In this article, we provide a brief summary to primary practitioners about the role bone markers can play in the management of osteoporosis.

Introduction

Osteoporosis is a major public health threat for an estimated 44 million Americans with direct national expenditure of $17 billion in 2001.^[1] In the US today, 10 million individuals are estimated to already have the disease and this figure is expected to climb to over 17 million by 2010 and 20 million by 2020. Of the 10 million Americans estimated to have osteoporosis, 8 million are women and 2 million are men. In addition, nearly 34 million Americans are estimated to have low bone mass, which puts them at increased risk of developing osteoporosis and related fractures.

Osteoporosis is defined as a skeletal disorder characterized by compromised bone strength^[2] predisposing to an increased risk of fracture. Consequently, deterioration in bone strength and fragility, in addition to decrease in bone mass and density, have been identified as factors that increase fracture risk. The diagnosis of osteoporosis is made by determining that the patient has a low bone density, usually by a Dual Energy X-ray Absortiometry^[3] (DEXA) measurement. This is important because a low bone density places a patient at increased risk for fracture,^[4,5] which is the ultimate adverse effect and main source of morbidity and mortality from osteoporosis disease. However, BMD is only one of the contributors to bone strength. The other main determinant of bone strength is derived from bone quality, which consists of bone mass, size, structure (micro-and macro-architecture), material properties, and bone remodeling.^[6] The issue of bone quality has recently received increasing attention because data from large clinical trials of anti-resorptive drugs have indicated that reduction in fracture risk or improvement in bone quality evoked by these drugs are only partly explained by increase in BMD.^[7,8] Several recent studies^{[6,9,10,11,12,13,14]} indicate a paradigm shift in exploring the underlying basis of this inconsistency by providing evidence that elevated bone remodeling activity accounts for a major fraction of both reduction in fracture risk and improvement in bone quality.^{[6,9,10,11,12,15]} In this regard, measurement of proteins and peptides, referred to as biochemical bone markers, that are released as a consequence of the physiological action of osteoblasts and osteoclasts provide the most practical tool currently available to measure bone remodeling in routine clinical practice. These bone biochemical markers can be found in the serum and urine and are categorized as markers of bone formation or bone resorption.^[16] It is of particular interest that measurement of bone biochemical markers may provide some assessment of factors that contribute to bone quality because the bone biochemical markers measure remodeling and, in general, a higher remodeling rate is detrimental to bone quality.^[15] Therefore, the best assessment of fracture risk may be made by bone density measurement along with the measurement of bone biochemical markers.

The remodeling or bone turnover occurs via a coupled process of bone resorption and bone formation. Bone resorption and bone formation are accomplished in a finely orchestrated sequence, initiated by osteoclasts, in front, followed by osteoblasts in a unit called 'basic multicellular unit' (BMU) [as shown in Figure 1(A-D)]. Individual BMUs maintain their integrity for approximately 4-8 months, with a range of 3 months-2 years^[17] It is believed that approximately one million BMUs are thought to be functioning in a healthy adult skeleton at any given time, replacing about 8%-10% of bone tissue annually, presumably to avoid loss of material properties and microdamages due to aging.^[18] In cancellous bone, BMUs create trenches as they move across the surface; in cortical bone, BMUs move through the bone matrix increasing porosity. During bone resorption, osteoclasts create resorption pits with low pH microenvironments, which dissolve the inorganic matrix exposing the organic matrix (> 90% of the organic matrix is composed of type-I collagen). Subsequently, bone-reabsorbing enzymes digest the organic bone matrix releasing breakdown products of type-I collagen, which include terminal peptide fragments from both ends of the type- I collagen such as N-terminal telopeptides called NTx,^[19] C-terminal telopeptides called CTx,^[20] and ring structures collectively called pyridinium crosslinks.^[21] Tests are now available that can specifically measure these collagen breakdown products. In healthy bone, the resorption cavity created by osteoclasts is completely filled with new osteoid material secreted by active osteoblasts during a reversal phase. The mesenchymal stem cells are attracted to BMU sites and differentiated into osteoblasts. The active osteoblasts secrete osteocalcin (OC), type-I pro-collagen peptides (N-terminal-PINP and C-terminal-PICP), and bone specific alkaline phosphatase (skeletal ALP); the concentration of OC, P1NP, P1CP, and skeletal ALP in serum is correlated with the bone formation rate.^[16] Bone formation is completed by mineralization, which occurs in two phases. The first phase occurs immediately after the formation of osteoid, when hydroxyapatite crystals are deposited between organic matrixes. The second phase involves a slower 'secondary mineralization' process that continues over months when more mineral is gradually added [Figure 1(C-D)]. Secondary mineralization increases the BMD, but not the volume, of new bone.^[22]

(Enlarge Image)

Figure 1.

Bone remodeling cycle and bone biochemical markers. The bone remodeling cycle is initiated by osteoclasts, which create resorption pits with low pH microenvironment (A), dissolves the inorganic matrix exposing the organic matrix (> 90% of the organic matrix is composed of type-I collagen). Then bone-reabsorbing enzymes digest the organic bone matrix releasing breakdown products of type-I collagen. The collagen breakdown products include terminal peptide fragments from both ends of the type-I collagen such as (N-terminal telopeptides - NTx, and C-terminal telopeptides - CTx) and a ring structure called deoxypyridinoline (DPD). Blood and urine levels of these collagen breakdown products indicate bone resorption rate. The normal bone turnover process creates resorption cavities, which are smoothed off by osteoblasts (B). The active osteoblasts secrete osteocalcin (OC), type- I pro-collagen peptides (N-terminal-PINP and C-terminal-PICP), and bone specific alkaline phosphatase (skeletal ALP); the concentration of OC, P1NP, P1CP, and skeletal ALP in serum is a measure of bone formation rate.^[16] Bone formation is completed by mineralization, which occurs in two phases. The first phase occurs immediately after the formation of osteoid, when hydroxyapatite crystals are deposited between organic matrixes. The second phase involves a slower 'secondary mineralization' process that continues over months when more mineral is gradually added (D).

Bone formation and bone resorption are usually balanced in healthy individuals who have adequate nutrition and exercise and attain normal puberty. Bone mass peaks at 30 years in both men and women and approximately 0.4% of bone is lost per year after this peak bone mass is achieved. In addition to this loss, approximately 1%-2% of bone is lost per year for the first 5-8 years after menopause.^[18] With menopause and aging, a coordinated balance in bone formation and resorption is disturbed, resulting in excessive bone loss and osteoporosis. The main factors that play important roles in pathogenesis of osteoporosis include increased: (1) frequency of BMU activation by up-regulation of osteoclasts; and (2) activity of osteoclasts. In addition, suppressed activity of osteoblasts and inadequate bone formation are the main causes of progression, thus providing opportunity for new therapeutic approaches to stimulate bone formation. In osteoporosis patients, how increased bone remodeling affects loss in bone strength is shown in Figure 1(A-D), the osteoclasts create more and excessively deep cavities (Figure 2B) resulting in: (1) increased porosity and significantly reduced bone strength in cortical bone; and (2) thinning of trabeculae and loss of trabecular connectivity in cancellous bone, reducing the bone strength by many fold. Excessive bone resorption creates small areas of clustered deep cavities that act as stress concentrators,^[23,24] which is analogous to a notch drawn (by a diamond cutter) on a glass plate to initiate a crack along a cutting line. Consequently, the stress concentrators represent a focal weakness, which signifycantly decreases the stress required to initiate fracture (shown in Figure 2). In addition, as horizontal trabeculae, which act as crossties slowly disappear due to increased remodeling, the thin unsupported vertical trabeculae are predisposed to buckling pressure. This loss of connectivity of horizontal trabeculae has a major impact on fracture risk independent of other factors affecting bone quality.^[25,26] Thus far, no direct evidence is available that directly relates bone marker levels with bone strength, however, high levels of bone resorption markers correlate with high rates of bone remodeling and therefore, theoretically bone markers can independently predict fracture risk. This concept also illustrates that small local losses of bone may not decrease much of the bone density but such losses can markedly decrease bone strength and thereby increase the risk for bone fracture.

(Enlarge Image)

Figure 2.

Small changes in bone turnover make large changes in bone strength. (A) Cross-section of a vertebral body from a normal person showing the pattern of spinal trabecular bone, and (B) that of a patient with osteoporosis showing the 'thinning' and loss of spinal trabecular bone, which compromises the overall mechanical strength of the bone. On the right hand panels, the illustrations show how high bone turnover affects trabecular bone micro-architecture and causes fractures. The normal bone turnover process creates resorption cavities, which are smoothed off by osteoblasts (A). In osteoporosis patients, the osteoclasts create more and excessively deep cavities (B) causing loss of trabecular connectivity, which is independently associated with fracture risk.^[25,26] In addition, small areas of clustered deep cavities on a thin unsupported vertical trabeculae act as stress concentrators,^[23,24] which significantly decrease the stress required for fracture (as shown in the example of a walking stick). This concept also illustrates that small local losses of bone may not decrease much of the bone density but markedly decrease the bone strength

It is important to note that because bone resorption and formation are coupled, an increase in either process will increase bone marker levels. In chronic steady-state conditions, most markers reflect both formation and resorption because only a small imbalance exists. In addition, biochemical markers are not disease specific, but reflect alterations in skeletal metabolism regardless of the underlying cause.

There are several reasons for familiarizing the primary care physicians with the role bone markers can play in the management of osteoporosis at this point in time:

Biochemical markers could be useful in making therapeutic decisions because, in general, the higher the bone remodeling and bone loss rates^[27,28] the greater the concentration of bone biochemical markers in blood or urine. This relationship appears to be continuous, with increasing levels of bone biochemical markers associated with progressively greater risk of rapid bone loss. Women generally lose about 1%-2% of their bone per year during and after menopause. However, nearly a third of postmenopausal women lose bone at a faster rate (3%-4% per year).^[27,28,29] Bone biochemical markers may detect these patients who are considered 'high bone turnover' patients who, are also most likely to respond to an osteoporosis therapy.^[28,29] A high turnover rate is detrimental to bone quality as explained above. In addition, a high bone turnover rate can reduce bone strength because old bone that has undergone more complete secondary mineralization is replaced by younger bone that has undergone primary, but less complete secondary, mineralization.^[12] The foregoing suggest that a higher rate of excretion of bone biochemical markers indicates a high bone turnover state, which is detrimental to bone strength thus bone markers may be potentially useful in identifying patients with increased risk of fracture.^[30]
At present BMD measurement is the best surrogate clinical marker of fracture risk, however, change in BMD during therapy is a poor predictor of fracture risk.^[7,8,10,11] The reduction in fracture risk explained by the observed changes in BMD by alendronate (6%-7% increase in BMD in the Fracture Intervention Trial),^[31] residronate (5%-6% increase in BMD in the Vertebral Efficacy With Residronate Therapy Study),^[32] raloxifene (2% increase in BMD in the Multiple Outcome of Raloxifene Evaluation study),^[33] and calcitonin (1.2% increase in BMD in the PROOF study)^[34] therapy is approximately 16%, 4%, 28%, and 8% respectively, indicating other factors contribute to bone strength and change with treatment. Several recent studies have shown^{[13,14,35,36]} that decreases in bone biochemical markers can account for 40%-70% of the observed anti-fracture efficacy. Data are beginning to accrue suggesting that changes in bone biochemical markers during treatment of osteoporosis patients can predict subsequent reductions in fracture risk^[13,14] independent of bone density by mechanisms that explain improvement in bone strength.^[37]
In the management of osteoporosis, changes in bone density generally can only be seen, on average, following about 2 years of treatment, whereas biochemical markers can provide dynamic information on the effectiveness of therapeutic agents within 3-6 months.^[38,39] Importantly, currently available osteoporosis therapies such as bisphosphonates, estrogens, SERMS, and calcitonins, act by reducing bone biochemical markers, thereby reducing the bone marker levels; hence, markers are useful in assessing efficacy of therapy.
Since November 2002, Medicare reimburses for several bone marker tests for both men and women.^[40]

In this article we review the potential utility of bone markers with respect to four general topics. (1) Why use bone markers in clinical practice? (2) Who should be tested? (3) How does one use bone markers in the therapeutic management of osteoporosis? (4) The use of a clinical algorithm regarding use of bone markers in the management of osteoporosis. As we discuss the value of bone markers in the management of osteoporosis, it should be noted that none of the markers are diagnostic for any particular bone disease nor are markers substitutes for BMD measurement. Furthermore, there are no prospective studies showing that the use of markers improves outcomes, such as fracture rate, morbidity, or mortality. Nevertheless, there is evidence that markers provide different information than bone density and their measurement can complement BMD to individualize patient management.