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Emory University School of Medicine, Atlanta, GA 30322.
a Address correspondence to: The Emory Clinic, Inc., 1365 Clifton Rd. NE, Atlanta, GA 30322. Fax 404-778-5230; e-mail nwatts{at}emory.edu
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Abstract |
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 Top Abstract IntroductionBone RemodelingComposition of BoneBone Resorption MarkersBone Formation MarkersProblems with MarkersGeneral Uses of Bone...Clinical ApplicationsCurrent Uses, Future DirectionsConclusionsReferences |
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Bone markers exhibit substantial short-term and long-term fluctuations related to time of day, phase of the menstrual cycle, and season of the year, as well as diet, exercise, and anything else that alters bone remodeling. These biological factors, in addition to assay imprecision, produce significant intra- and interindividual variability in markers.
Bone marker measurements are noninvasive, inexpensive, and can be repeated often. Unfortunately, most of the studies that provided insight on clinical situations did not focus on markers as a primary endpoint. Bone markers have been useful in clinical practice and have been helpful in understanding the pathogenesis of osteoporosis and the mechanism of action of therapies. In clinical trials, markers aid in selecting optimal dose and in understanding the time course of onset and resolution of treatment effect. Clinical questions that might be answered by bone markers include diagnosing osteoporosis, identifying "fast bone losers" and patients at high risk of fracture, selecting the best treatment for osteoporosis, and providing an early indication of the response to treatment. Additional information is needed to define specific situations and cut points to allow marker results to be used with confidence in making decisions about individual patients.© 1999 American Association for Clinical Chemistry
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Introduction |
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TopAbstractIntroductionBone RemodelingComposition of BoneBone Resorption MarkersBone Formation MarkersProblems with MarkersGeneral Uses of Bone...Clinical ApplicationsCurrent Uses, Future DirectionsConclusionsReferences |
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There are two basic types of bone: cortical, or compact bone, is well suited to the supporting, protective, and mechanical functions of bone. Cortical bone makes up the shafts of the long bones (appendicular skeleton) and the outer envelope of all bones and constitutes ~80% of skeletal mass. Cancellous, or trabecular, bone has a lacy or honeycombed structure well suited as a site for bone-forming cells and a large surface area that provides a reservoir for minerals. Cancellous bone makes up the inner parts of the bones of the vertebrae and pelvis and the ends of the long bones (the axial or central skeleton).
Bone remodeling, also called bone turnover, is an essential part of bone health. With daily activities, bone sustains microfractures and fatigue damage that must be repaired for bone to remain strong. Without remodeling, the skeleton would eventually collapse.
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Bone Remodeling |
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TopAbstractIntroductionBone RemodelingComposition of BoneBone Resorption MarkersBone Formation MarkersProblems with MarkersGeneral Uses of Bone...Clinical ApplicationsCurrent Uses, Future DirectionsConclusionsReferences |
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). The cycle begins with recruitment from bone marrow monocyte
precursors of multinucleated bone-resorbing cells called osteoclasts,
which attach to the surface of bone. A ruffled border develops beneath
the osteoclast, sealing the space beneath the cell. Into this
subcellular space the osteoclast generates hydrogen ions, lactate, and
proteolytic enzymes, which cause a breakdown of the protein matrix of
bone and release of calcium and other bone mineral constituents. After
the osteoclasts have excavated a resorption pit or lacuna, bone-forming
cells called osteoblasts differentiate from connective-tissue
precursors and begin the process of filling in the lacuna with a
protein matrix, called osteoid, which subsequently becomes fully
mineralized new bone.
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Remodeling is regulated by both local and systemic factors, including electrical and mechanical forces, hormones (e.g., parathyroid hormone, thyroid hormone, vitamin D and its metabolites, estrogen, androgens, cortisol, calcitonin, and growth hormone), growth factors [e.g., insulin-like growth factor 1 (IGF-1) and transforming growth factor ß], and cytokines (e.g., interleukins 1 and 6). Remodeling takes place only on the surface of bone and in closely coordinated local packets. The cells involved in a particular remodeling event are referred to as a basic multicellular unit or bone metabolic unit (BMU). In a typical remodeling cycle, resorption takes ~7–10 days, whereas formation requires 2–3 months. Overall, ~10% of bone is replaced each year. However, remodeling occurs exclusively on bone surfaces. Cancellous bone makes up only ~20% of the skeletal mass, but 80% of the surface is cancellous bone. Because of this, cancellous bone is more metabolically active and more rapidly remodeled than cortical bone. Approximately 25% of cancellous bone is renewed each year, compared with only ~3% of cortical bone.
The process of bone remodeling is often referred to as being "coupled". Coupling means that bone formation is linked to bone resorption, and with rare exceptions, bone formation must be preceded by bone resorption. Coupling should not to be confused with balance, which implies that the amount of bone that is removed is completely replaced. In fact, after age 35–40, every time a remodeling cycle is completed there is a net loss of bone because the amount of bone formed is less than the amount removed by resorption. Estrogen deficiency and other abnormalities of skeletal regulation will greatly increase the rate of remodeling and accentuate this imbalance.
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Composition of Bone |
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TopAbstractIntroductionBone RemodelingComposition of BoneBone Resorption MarkersBone Formation MarkersProblems with MarkersGeneral Uses of Bone...Clinical ApplicationsCurrent Uses, Future DirectionsConclusionsReferences |
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The state of the skeleton can be evaluated by a variety of techniques, including histomorphometry, densitometry, and measurement of calcium fluxes. Histomorphometry is invasive, expensive, has a long turnaround time, and is limited to a single skeletal site (iliac crest). Densitometry is precise and noninvasive but slow to reveal changes. Measurement of calcium fluxes is technically difficult. Biochemical markers of bone remodeling provide a noninvasive means of complimenting these techniques or providing direct information. Markers respond to intervention more rapidly than does densitometry.
Biochemical markers that reflect the remodeling process and can be measured in blood or urine fall into three categories: (a) enzymes or proteins that are secreted by cells involved in the remodeling process, (b) breakdown products generated in the resorption of old bone, and (c) byproducts produced during the synthesis of new bone. Because of the phenomenon of coupling, these markers reflect the general process of bone turnover when bone is in a steady state; however, markers are usually classified by the part of the remodeling process that they mainly reflect in acute situations (i.e., resorption or formation). Because the process of resorption is shorter than the process of formation, resorption markers respond faster to changes in remodeling than do formation markers.
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Bone Resorption Markers |
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TopAbstractIntroductionBone RemodelingComposition of BoneBone Resorption MarkersBone Formation MarkersProblems with MarkersGeneral Uses of Bone...Clinical ApplicationsCurrent Uses, Future DirectionsConclusionsReferences |
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).
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Urinary calcium is affected by diet and renal function and is not sufficiently sensitive or specific for assessment of bone remodeling.
trap
Acid phosphatase is a lysosomal enzyme found in bone, prostate,
platelets, erythrocytes, and spleen. Of the five isoenzymes of acid
phosphatase, the bone isoform is tartrate resistant (TRAP) but
unstable. TRAP can be measured in serum or plasma by electrophoresis
(after treatment with tartrate) or by immunoassay. Serum acid
phosphatase concentrations are typically higher than those in plasma
because of the release of acid phosphatase from erythrocytes during
clotting.
collagen breakdown products
Type 1 collagen, rich in the amino acid hydroxyproline, has a
triple helix structure, with strands connected by cross-links between
lysine or hydroxylysine residues that join the nonhelical amino- and
carboxy-terminal ends of one collagen molecule to the helical portion
of an adjacent molecule (1). The cross-links are
pyridinolines and deoxypyridinolines (Fig. 2
). During bone resorption, hydroxyproline and the pyridinium
cross-links may be released either free or with fragments of the
collagen molecule attached. They are not reutilized. Although some type
1 collagen is present in nonskeletal tissues, bone has a much higher
proportion and a much higher turnover.
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Hydroxyproline.
Collagen is rich in the amino acid proline,
which undergoes posttranslational hydroxylation to hydroxyproline. Most
of the free hydroxyproline liberated from bone is catabolized in the
liver; ~10% is released in small polypeptide chains that are
excreted in the urine. Hydroxyproline is also liberated by the
breakdown of complement and nonskeletal collagen, including dietary
collagen, and by the breakdown of procollagen extension peptides, which
are products of bone formation. Approximately 50% of urinary
hydroxyproline is derived from bone collagen breakdown (2).
Hydroxyproline is usually measured in urine by colorimetry or
HPLC after hydrolysis to convert peptide and polypeptide forms
to the free form.
Pyridinium cross-links (pyridinoline and deoxypyridinoline).
Posttranslational modification of lysine and hydroxylysine
produces the nonreducible pyridinium cross-links, pyridinoline (Pyr)
and deoxypyridinoline (Dpd), that stabilize mature collagen. Both Pyr
and Dpd are released from bone in a ratio of approximately 3:1. Dpd is
relatively specific for bone; Pyr is also found in articular cartilage
and in soft tissues (ligaments and tendons). Approximately 60% of the
cross-links released during resorption are bound to protein, with the
remaining 40% being free (not protein bound). Pyridinium cross-links
are not metabolized or absorbed from the diet (3). Pyr and
Dpd can be measured in urine by HPLC or immunoassay (4)(5)(6)(7)(8)
either before or after hydrolysis.
Cross-linked telopeptides.
In the process of bone resorption,
amino- and carboxy-terminal fragments of collagen are released
with cross-links attached. These fragments with attached cross-links
are called telopeptides. N-telopeptides (NTx) and C-telopeptides (CTx)
are excreted in the urine. NTx is measured by immunoassay using an
antibody to the 
-2 chain of the NTx fragment (which contains the
pyridinium cross-links, but the assay does not recognize the cross-link
itself) (9). CTx is measured by immunoassay (10).
Urine has been the most convenient sample for assay, but efforts have
been directed at developing serum assays (11)(12)(13)(14).
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Bone Formation Markers |
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TopAbstractIntroductionBone RemodelingComposition of BoneBone Resorption MarkersBone Formation MarkersProblems with MarkersGeneral Uses of Bone...Clinical ApplicationsCurrent Uses, Future DirectionsConclusionsReferences |
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).
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alkaline phosphatase
Osteoblasts are rich in alkaline phosphatase; however, alkaline
phosphatase, an enzyme associated with the plasma membrane of cells, is
also found in liver, intestine, and placenta (15), all of
which may contribute to the total amount of alkaline phosphatase found
in blood. The bone isoenzyme predominates in childhood and particularly
during puberty; however, in adults the bone and liver isoenzymes
contribute approximately equally to the total, with the intestinal
fraction accounting for <10%. The function of alkaline phosphatase is
unknown. The condition hypophosphatasia, in which the enzyme is
lacking, is characterized by osteomalacia, suggesting that alkaline
phosphatase has a role in the mineralization of newly formed bone.
Measurement of total serum alkaline phosphatase is useful when the
amount from bone is exceptionally high (such as in Paget disease
of bone) and concentrations from other sources are not increased and
are stable. Because of the multiple sources of origin and the fact that
the bone isoform is usually not increased in osteoporosis and other
metabolic bone diseases, total alkaline phosphatase has not enjoyed
widespread use as a bone remodeling marker.
Bone, liver, and intestinal isoforms of alkaline phosphatase are posttranslational modifications of the same gene product and can be identified by their unique carbohydrate content (16). Measurement of "fractionated" alkaline phosphatase recognizes that heating destroys the skeletal fraction, which can be determined by subtraction of the stable fraction from the total. This procedure is not sufficiently reproducible to be used clinically. Assays for bone alkaline phosphatase [BAP; also known as bone-specific alkaline phosphatase, or skeletal alkaline phosphatase (SAP)] have been developed using electrophoresis, isoelectric focusing, lectin precipitation, and immunoassay techniques. Immunoassay is the method of choice because of high specificity and satisfactory precision. Commercially available immunoassays have been developed that measure either enzyme activity or mass (17)(18)(19). Because BAP is cleared by the liver, the skeletal fraction may be increased in patients with liver diseases. There may also be some cross-reaction of BAP antibodies with liver alkaline phosphatase.
osteocalcin
Osteocalcin, the major noncollagen protein of bone matrix, is a
small 49-amino acid protein that is rich in glutamic acid (GLA)
(20). Osteocalcin is also known as bone GLA protein and
BGP. In addition to bone, it is also found in dentin. The
function of osteocalcin is not clear; it may serve as a site for
hydroxyapatite crystals. In the process of matrix synthesis, some
osteocalcin is released and circulates in blood with a short half-life
determined mainly by renal clearance. Although no intact osteocalcin is
released during bone resorption, fragments are released in vitro and
also during resorption and formation (Fig. 3
) (21)(22)(23). Osteocalcin can be measured by
immunoassay in plasma or serum. Osteocalcin is labile in blood. It is
reduced in lipemic serum because of binding of osteocalcin to lipids,
and osteocalcin may be degraded in vitro by proteolytic enzymes
liberated from erythrocytes. Assays for osteocalcin are not
standardized (24), and different antibodies clearly
recognize different fragments (25)(26).
Antibodies that recognize both the intact molecule and the large
N-terminal midmolecule fragment appear to provide the best clinical
information (27).
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Although vitamin K status does not affect the total-osteocalcin concentration, it does affect the amount of carboxylation. Undercarboxylated osteocalcin may be a better predictor of certain outcomes such as fracture (28)(29).
procollagen extension peptides
Osteoblasts secrete large procollagen molecules that undergo
extracellular cleavage at the amino and carboxy termini. Byproducts of
type 1 collagen synthesis are the amino- and carboxy-terminal
procollagen 1 extension peptides (PINP and PICP)
(14)(30)(31)(32)(33). PINP is an elongated protein of 35
kDa. PICP is a globular protein of 1000 kDa and contains disulfide
bodes. Both extension peptides are cleared by the liver. Both may be
incorporated into bone matrix. Both can be measured by immunoassay. The
concentrations of both increase with increased turnover of nonskeletal
collagen (e.g., skin and muscle).
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Problems with Markers |
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TopAbstractIntroductionBone RemodelingComposition of BoneBone Resorption MarkersBone Formation MarkersProblems with MarkersGeneral Uses of Bone...Clinical ApplicationsCurrent Uses, Future DirectionsConclusionsReferences |
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Unfortunately, the ideal marker does not exist. Although changes in remodeling can be extreme, as in Paget disease or renal osteodystrophy, the changes are usually rather subtle, as in osteoporosis.
factors responsible for variability and fluctuations in bone
markers
Bone remodeling varies in a diurnal rhythm; changes with the phase
of the menstrual cycle and the season of the year; is altered by bed
rest, exercise, and extremes of diet; and basically is affected by
anything that alters bone remodeling. Neither baseline nor
posttreatment values for bone markers in the "normal" population
follow a gaussian distribution. An individual's rate of
remodeling may vary over time.
Urinary excretion of Dpd is 50–70% higher at night than in the morning (34)(35). Similar fluctuations are seen for other resorption markers. Diurnal variation is less of a factor for alkaline phosphatase (36) and osteocalcin (37) because they have longer half-lives. Diurnal change is not influenced by posture, age, menopause, or osteoporosis (38). The day-to-day variation is ~10% for formation markers and 20% for resorption markers. During the menstrual cycle, marker concentrations are slightly higher in the luteal phase (39). There can be a seasonal change of up to 12%, with values higher in winter than summer (40). Marker concentrations increase during puberty and again after menopause. They are low in late pregnancy (41). After fracture, marker concentrations go up 20–60% and remain high for 6 months or more. With weightlessness or prolonged bed rest, markers increase by 40–50% (42), but the patterns of recovery vary depending on the marker (43).
Markers are only relatively specific for bone. Alkaline phosphatase is derived from nonskeletal sources, and osteocalcin fragments may reflect both resorption and formation. Osteocalcin and BAP give discordant results in conditions such as Paget disease and renal osteodystrophy (44).
Metabolism and the clearance of markers influence their concentrations. For example, the proportions of different fragments of osteocalcin depend on renal function. Liver clearance affects BAP; renal clearance affects NTx, CTx, and pyridinium cross-links (45). Another factor affecting urinary bone markers, which are usually normalized to creatinine, is the variability of creatinine excretion (46).
When there is a change in the rate of remodeling, resorption markers fall faster than formation markers (2–12 weeks for resorption markers, 3–6 months for formation markers) because of the shorter time of resorption than formation.
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General Uses of Bone Markers |
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TopAbstractIntroductionBone RemodelingComposition of BoneBone Resorption MarkersBone Formation MarkersProblems with MarkersGeneral Uses of Bone...Clinical ApplicationsCurrent Uses, Future DirectionsConclusionsReferences |
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Multiple or duplicate measurements can be used to minimize the effect of intraindividual variation. Another approach is calculation of the "least significant change" or "critical difference", which incorporates the biological and analytical variation (49). At P <0.05, using a one-tailed approach, the least significant change is 2.33 times the individual CV. It is in the range of 15% for BAP (50) and osteocalcin (51), and 25–40% for Pyr (49)(51)(52), Dpd (49)(51)(52), and NTx (53)(54).
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Clinical Applications |
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TopAbstractIntroductionBone RemodelingComposition of BoneBone Resorption MarkersBone Formation MarkersProblems with MarkersGeneral Uses of Bone...Clinical ApplicationsCurrent Uses, Future DirectionsConclusionsReferences |
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which patients have low bone mass?
Although bone is a dynamic tissue, studies that have examined the
relationship between turnover markers and bone density in young
individuals have shown either a weak correlation or none at all
(55)(56). The relationship is somewhat stronger
in elderly women, but not strong enough to allow the use of a bone
marker measurement to identify individuals with low bone mass
(57)(58).
which patients are likely to lose bone?
At least two studies have suggested that change in bone mass over
time correlates with the concentrations of markers
(59)(60). In both of these studies, markers were
measured at the end of the observation period. In a prospective study,
Chesnut et al. (61) found a modest correlation between
baseline urine NTx and the rate of bone loss during the following year
in recently menopausal women (Fig. 4
). However, no correlation has been seen between baseline bone
markers and future bone loss in large prospective studies such as the
Postmenopausal Estrogen-Progestin Intervention (PEPI) (62),
the Fracture Intervention Trial (63), the Phase III
alendronate study (Fig. 5
) (64), and other prospective trials
(65)(66).
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is this patient at high risk of fracture?
A French study, Epidemiologie de L'osteoporose (EPIDOS),
evaluated 7598 elderly women and showed correlations between high
concentrations of the resorption markers urine CTx and free Dpd and
increased hip fracture risk similar in magnitude to that between low
hip bone mineral density (BMD) and increased hip fracture risk
(67). For urine CTx more than 2 SD above the premenopausal
mean, the sensitivity in predicting hip fracture was 36% and the
specificity was 81% (64% false negatives and 19% false positives);
however, the positive predictive value was only 3%. The correlation
was not seen for all resorption markers and was not seen at all for
formation markers. Similar findings for the resorption markers total
Pyr, free Pyr, total Dpd, and free Dpd in relation to hip fracture
emerged from the Rotterdam Study (68), which involved
10 275 men and women 55 years and older. In EPIDOS (67),
the combination of low hip BMD and high resorption marker concentration
gave greater predictive value for hip fracture than either risk factor
alone. However, the number of patients in EPIDOS who fell into the
high-risk categories for both of these variables was small (only 16%
of the total sample). A relationship between previous fractures and
increased Pyr and osteocalcin was seen in a cross-sectional study of
351 women in Rochester, MN (56). Most of the Rochester women
with osteoporosis had high bone turnover.
if treatment is needed, what treatment would be best?
A study of calcitonin treatment for osteoporosis found a dramatic
improvement in bone mass in patients who had high bone turnover, and no
change in patients who had normal or low turnover (69). In
this study, turnover was measured not with biochemical markers, but
rather by whole body retention of radiolabeled bisphosphonate. Whether
the same result would be seen with markers is uncertain. Because
all of the current therapies in use, at least in the US, work by
decreasing bone resorption, this question may not be of practical value
at present. However, it could be important once bone-anabolic
medications are available.
is the patient responding to treatment?
Chesnut et al. (61) found a fairly strong relationship
(r = 0.25; P <0.01) between baseline urine
NTx and BMD response to 1 year of hormone replacement therapy in
recently menopausal women (Fig. 6
). Greenspan et al. (70) found a similar relationship
between urine NTx and BMD response to alendronate. However, other
investigators have failed to find consistent correlations between
baseline marker concentrations and changes in BMD after treatment with
estrogen (62) or alendronate (Fig. 7
) (63)(64)(71).
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If baseline markers fail to predict changes in BMD with treatment, perhaps changes in the concentrations of markers soon after initiation of treatment would predict later changes in BMD. Women receiving hormone replacement therapy who had the greatest decline in NTx at 6 months had the greatest increase in BMD at 1 year (61). A 30% decrease in NTx at 6 months had 80% sensitivity and 59% specificity, with 80% positive and 42% negative predictive values. However, the range of change in urine NTx from baseline to 6 months in the treated group was +192% to -87%. In the same study, correlations were also seen between 6-month changes in free Dpd and BAP and an increase in BMD at 1 year (72). However, these relationships were not confirmed with hormone replacement therapy in the PEPI trial (62). Changes in marker concentrations have been shown to correlate with increases in BMD after alendronate treatment in some studies (70)(73) and with ibandronate (74). The correlations, however, are too weak to use markers to identify "high gainers" vs "low gainers". Of interest, at least with bisphosphonate treatment, is that total and bound Pyr and Dpd decrease substantially but free Pyr and Dpd do not (75).
Different markers exhibit different degrees of change with bisphosphonate therapy (76). NTx showed the greatest decline (58%), but also had the greatest long-term variability (29.5%). BAP was the marker that showed greater than the minimum significant change in the highest number of patients (74%), compared with 57% of patients using NTx or 48% of patients using free Dpd.
There are no published data on BMD change in treated individuals who do not show a change in markers or about marker change in patients who lose bone despite being on treatment. Finally, there is some information suggesting that the change in BMD may not reflect a change in fracture risk (77). If this is true, it would render moot the search for a marker correlation with BMD change after treatment. On the other hand, if the change in fracture risk is related to both changes in bone mass and changes in bone turnover, as suggested by Riggs et al. (78), markers may become a very important tool for assessing the response to treatment.
The use of bone markers in clinical practice is limited by the lack of studies done with markers as the primary endpoint. Most of the information comes from clinical trials of osteoporosis therapies, in which the endpoints were increases in BMD and markers were measured secondarily. Only a few studies have had a decrease in fracture rates as the main endpoint, and none of them specifically examined the relationship between the occurrence of fractures and baseline marker concentrations or between fractures and the change in marker concentrations with treatment. Almost all of the positive data are from studies of elderly women. Although there are some normative data in young women and in men (79), there are essentially no data to guide the use of markers in men or younger women.
Because of a paucity of data, it is difficult for the clinician to know which marker to measure, when to measure it (i.e., baseline or after treatment), and what cut points to use. For almost all of the clinical questions that might be answered with bone markers, positive and negative predictive values are on the order of 70–80%, with false-negative and false-positive results in 20–30% of patients.
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Current Uses, Future Directions |
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TopAbstractIntroductionBone RemodelingComposition of BoneBone Resorption MarkersBone Formation MarkersProblems with MarkersGeneral Uses of Bone...Clinical ApplicationsCurrent Uses, Future DirectionsConclusionsReferences |
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Continued research is needed to identify the best marker or combinations of markers for prediction of treatment response (either a change in BMD or antifracture effect) and for prediction of bone loss or fracture in untreated patients. It is not clear that a measurement today will predict BMD or fracture 10 or 20 years in the future. Certainly, efforts at standardization of methods and reduction of preanalytic and analytic variables are important. The use of assays in serum, sweat, or saliva might minimize some of the variability seen with urine markers.
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Conclusions |
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TopAbstractIntroductionBone RemodelingComposition of BoneBone Resorption MarkersBone Formation MarkersProblems with MarkersGeneral Uses of Bone...Clinical ApplicationsCurrent Uses, Future DirectionsConclusionsReferences |
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Footnotes |
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References |
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TopAbstractIntroductionBone RemodelingComposition of BoneBone Resorption MarkersBone Formation MarkersProblems with MarkersGeneral Uses of Bone...Clinical ApplicationsCurrent Uses, Future DirectionsConclusionsReferences |
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H. W. Vesper, L. M. Demers, R. Eastell, P. Garnero, M. Kleerekoper, S. P. Robins, A. K. Srivastava, G. R. Warnick, N. B. Watts, and G. L. Myers Assessment and Recommendations on Factors Contributing to Preanalytical Variability of Urinary Pyridinoline and Deoxypyridinoline Clin. Chem., February 1, 2002; 48(2): 220 - 235. [Abstract] [Full Text] [PDF]
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 J. M. Brown, R. L. Vessella, P. J. Kostenuik, C. R. Dunstan, P. H. Lange, and E. Corey Serum Osteoprotegerin Levels Are Increased in Patients with Advanced Prostate Cancer Clin. Cancer Res., October 1, 2001; 7(10): 2977 - 2983. [Abstract] [Full Text] [PDF]
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R. Okabe, K. Nakatsuka, M. Inaba, T. Miki, H. Naka, H. Masaki, A. Moriguchi, and Y. Nishizawa Clinical Evaluation of the Elecsys {beta}-CrossLaps Serum Assay, a New Assay for Degradation Products of Type I Collagen C-Telopeptides Clin. Chem., August 1, 2001; 47(8): 1410 - 1414. [Abstract] [Full Text] [PDF]
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L.-o. Chailurkit, B. Ongphiphadhanakul, N. Piaseu, S. Saetung, and R. Rajatanavin Biochemical Markers of Bone Turnover and Response of Bone Mineral Density to Intervention in Early Postmenopausal Women: An Experience in a Clinical Laboratory Clin. Chem., June 1, 2001; 47(6): 1083 - 1088. [Abstract] [Full Text] [PDF]
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J. R. Berenson, R. A. Vescio, L. S. Rosen, J. M. VonTeichert, M. Woo, R. Swift, A. Savage, E. Givant, M. Hupkes, H. Harvey, et al. A Phase I Dose-ranging Trial of Monthly Infusions of Zoledronic Acid for the Treatment of Osteolytic Bone Metastases Clin. Cancer Res., March 1, 2001; 7(3): 478 - 485. [Abstract] [Full Text]
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, Dpd; 
, Pyr.
