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Use of biochemical markers of bone turnover in osteoporosis
Hillel N Rosen, MD
UpToDate performs a continuous review of over 375 journals and other resources. Updates are added
as important new information is published. The literature review for version 15.3 is current through
August 2007; this topic was last changed on January 2, 2007. The next version of UpToDate (16.1)
will be released in March 2008.
INTRODUCTION — Biochemical markers of bone turnover have little value for the diagnosis of
osteoporosis, because radiographic techniques are far superior for this purpose. However, markers of
bone turnover may give some indication about the future risk for bone loss and fractures. More
importantly, they are useful in monitoring the efficacy of antiresorptive therapy in patients with
osteoporosis.
This topic will review these issues. The rationale for the use of biochemical markers and the meaning
of the different markers are discussed separately. (See "Bone physiology and biochemical markers of bone
turnover").
DIAGNOSIS — The mean values for biochemical markers of bone turnover are higher in patients with
osteoporosis than in matched normal subjects. As an example, the mean urinary excretion of
deoxypyridinoline crosslinks (DPD, a marker of bone resorption) is 20 to 100 percent higher in
patients with osteoporosis than in normal subjects [1-4]. The results of measurements of other
markers are similar [1-3,5].
In addition, bone mineral density in patients with osteoporosis is inversely related to the levels of
markers of bone turnover. One study, for example, found a highly significant correlation between
serum osteocalcin concentrations (a marker of bone formation) and bone mineral density of the spine
[6]. Another report divided subjects into quartiles according to the urinary excretion of cross-linked Ntelopeptides (NTX) of type 1 collagen, a marker of bone resorption [7]. There was an inverse
relationship between the quartile of urinary N-telopeptide excretion and mean bone mineral density
(show figure 1). These findings are consistent with the concept that osteoporosis is characterized by an
increase in both bone formation and resorption (show table 1). (See "Pathogenesis of osteoporosis").
Despite these general trends, biochemical markers are not useful in making the diagnosis of
osteoporosis because the values in normal subjects and patients with osteoporosis overlap
substantially (show figure 2). In one report, for example, patients with low serum osteocalcin
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concentrations had bone densities that ranged from low to very high (show figure 3). For these
reasons, we do not recommend measurements of markers of bone turnover to make a diagnosis of
osteoporosis.
PREDICTING FUTURE RISK FOR BONE LOSS AND FRACTURE — A patient's current bone density is an
important predictor of fracture risk [8,9]. However, a single measurement indicates only current
density, not the anticipated rate of bone loss. Patients with a given bone density who are losing bone
more rapidly will have a higher fracture risk.
Some studies have demonstrated that markers of bone turnover may be useful in predicting rates of
future bone loss, and may therefore provide information about fracture risk beyond that available
from measurements of bone density. In most studies there is a highly significant correlation between
markers of bone turnover and subsequent rates of bone loss (show figure 4) [10-15]. Once again,
however, the diagnostic utility of a single measurement of bone turnover is limited because patients in
whom bone turnover is low have rates of bone loss that range from 0 to 10 percent/year [10].
Nonetheless, patients with a high value of a marker of bone turnover are at higher risk for bone loss
than those with a low value.
Thus, women with low bone density or high marker values would be at risk for osteoporosis and
therefore warrant preventive measures [16,17]. The potential validity of this approach can be
illustrated by the following results:
A prospective case-control study found that for every 1 SD elevation of urinary free DPD excretion,
the risk of hip fracture was fourfold higher even after adjusting for age and bone density [18].
●
Women with urinary free DPD excretion above the normal limits for young women have twice the
risk of fracture as compared with other women, even after adjusting for bone density; the risk is
further increased if bone density is low (show figure 5) (show figure 2) [19]. In another study, high
values for urine and serum type I collagen C-telopeptides (CTX) and for serum bone alkaline
phosphatase were similarly predictive of fracture [20]. In a third prospective study, serum CTX,
osteocalcin, and TRAP predicted risk of vertebral fractures [21].
●
Women with the highest bone turnover appear to gain the most BMD from antiresorptive therapy
with estrogen [12], calcium [12], or calcitonin (show figure 6) [22].
●
In comparison, menopausal women whose urinary NTX excretion is in the lowest quartile (<38) lose
little bone [12].
●
In risedronate trials, the relative risk of vertebral fracture after one year of risedronate therapy was
similar in subjects with either high or low pretreatment bone turnover as measured by urinary DPD
(RR 0.28 and 0.33 for high and low turnover groups versus placebo, respectively) [23]. However, the
absolute risk reduction was greater in the high compared with the low turnover group (7.1 and 4
percent reduction, respectively).
●
In alendronate trials [24,25], baseline markers were not predictive of bone loss or subsequent risk of
fracture [24]. However, patients with the highest tertile of baseline levels of BSAP and PINP had
greater fracture reduction than patients with the lowest tertile of those levels.
●
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Recommendation — We recommend that bone density be measured if preventive therapy is being
contemplated for women at risk for osteoporosis (eg, at menopause): Women with osteoporosis (T<2.5) should be treated, while women with normal values (T>-1) should not. One should consider
treating women with osteopenia (-1>T>-2.5) only if their bone turnover is above the upper limits of
normal for premenopausal women. If, for example, a newly postmenopausal woman had an
intermediate bone density and her urinary NTX excretion were low, antiresorptive therapy could be
withheld for two to year years from the viewpoint of bone protection. Bone density should be
measured again at two years to be sure that the expectation of slow bone loss was correct.
USE IN MONITORING EFFICACY OF ANTIRESORPTIVE THERAPY — The mean bone density in women
receiving therapy with antiresorptive agents such as estrogen or a bisphosphonate is stable or
increases slightly (show figure 7A-7B). However, some women continue to lose bone while receiving
antiresorptive therapy. This has been estimated to occur in approximately one-third of women
receiving estrogen (show figure 8) and one-sixth of those receiving alendronate [26,27].
Monitoring — Women taking antiresorptive therapy should be monitored to make sure the therapy is
having the desired effect [28]. One approach is to monitor bone density at baseline and again after
two years of therapy. However, this approach would not detect failure of therapy for a long time.
A second approach involves measuring bone density and a marker of bone turnover at baseline,
followed by a repeat measurement of the marker after six months of antiresorptive therapy. A
decrease of greater than 50 and 30 percent in urinary NTX excretion and serum carboxy-terminal
collagen crosslinks (CTX), respectively, provides evidence of compliance and drug efficacy [29-32]; in
such patients, therapy should be continued for two years, when bone density can be measured again.
This approach is supported by the observations:
In the MORE trial, fracture risk with raloxifene therapy correlated better with changes in markers of
bone turnover than with improvements in bone mineral density [33,34].
●
In risedronate vertebral fracture trials, the greatest decrease in fracture risk was among subjects
with a decrease in urine NTX of more than 40 percent and urine CTX of more than 60 percent (show
figure 9) [35]. No further improvement in fracture risk was found with further suppression of turnover.
If urinary NTX excretion falls by 40 to 50 percent after initiating therapy, one can be reasonably sure
that the woman will not lose bone while receiving this therapy.
●
Choice of marker — There is controversy regarding which markers provide the most useful
information about the subsequent risk of fractures in untreated patients and the decrease in bone loss
and fracture risk in treated patients.
The EPIDOS study found that, among elderly women, urinary DPD excretion above the upper limit
of normal for premenopausal women approximately doubled the fractured risk in untreated women; in
contrast, urinary NTX excretion was not predictive [19]. Similarly, analysis of the placebo arm of the
VERT trial found that urinary DPD (by HPLC) levels >median doubled the risk of vertebral fractures at
one year [23].
●
In a prospective study of newly postmenopausal women, high baseline urinary NTX excretion
predicted both rapid bone loss in women who were not treated and significant bone gain in those
●
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given estrogen [36]. Low baseline urinary NTX excretion predicted little bone loss without and little
benefit with estrogen therapy. Similarly, women receiving calcium supplementation who were in the
highest quartile urinary NTX excretion at baseline had a significantly greater decrease in spine bone
density over the course of one year than women with the lowest baseline values (show figure 10).
Urinary DPD values were not predictive of subsequent bone loss.
A third report of postmenopausal women treated with alendronate found that at six months after the
start of therapy, a 40 percent or greater decrease in urinary NTX or a 20 percent or greater decrease
in serum osteocalcin predicted either stabilization or an increase in bone density at two years [32]. On
the other hand, reductions in these markers below these cutoffs were not predictive of bone loss
during alendronate therapy.
●
Serum, as well as urinary, markers of bone turnover may be useful for monitoring the response to
therapy. As an example, in a placebo-controlled study of alendronate in 120 elderly women,
decreases in serum NTX and CTX at six months correlated with improvements in vertebral density at
2.5 years in the alendronate group [37].
●
No monitoring — A third approach to monitoring takes the position that monitoring for efficacy of
antiresorptive therapy is unnecessary. Although not all women are perfectly protected, there is no
evidence that we can improve outcome in those who do not respond well to therapy. We do not know
if they are best served by increasing the dose of the antiresorptive agent, switching therapy, adding a
second antiresorptive agent (eg, alendronate to estrogen), or simply continuing therapy, assuming
they would lose more bone mass if therapy was stopped.
Recommendation — Although the optimal approach is uncertain, we recommend the second approach
in which monitoring with markers is performed. We measure either urinary NTX or serum CTX and
look for a 50 percent decline with therapy as an index of adequate treatment. Follow-up with a
measurement of bone density in two to three years, to make sure that the predictions about bone loss
were correct, is advised.
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Rosen, HN, Moses, AC, Garber, J, et al. Serum CTX: a new marker of bone resorption that shows
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Sarkar, S, Reginster, JY, Crans, GG, et al. Relationship between changes in biochemical markers of
bone turnover and BMD to predict vertebral fracture risk. J Bone Miner Res 2004; 19:394.
Eastell, R, Barton, I, Hannon, RA, et al. Relationship of early changes in bone resorption to the
reduction in fracture risk with risedronate. J Bone Miner Res 2003; 18:1051.
Rosen, CJ, Chesnut III, CH, Mallinak, NJS. The predictive value of biochemical markers of bone
turnover for bone mineral density in early postmenopausal women treated with hormone
replacement or calcium supplementation. J Clin Endocrinol Metab 1997; 82:1904.
Greenspan, SL, Rosen, HN, Parker, RA. Early changes in serum N-telopeptide and C-telopeptide
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GRAPHICS
NTX excretion bone density
Inverse relationship between the quintile of urinary N-telopeptide
excretion and bone mineral density
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Mean total hip bone mineral density (left panels) and lumbar spine bone mineral
density (right panels) decrease with increasing quintiles of urinary N-telopeptide
(NTX) excretion in 374 men (top), 223 women taking estrogen (center), and 364
women not taking estrogen (bottom). Data from Schneider, DL, Barrett-Connor, EL,
Arch Intern Med 1997; 157:1241.
Causes of osteoporosis
Causes of osteoporosis according to probable mechanism
High turnover - increased bone resorption greater than increased bone formation
Estrogen deficiency - primarily in postmenopausal women
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Hyperparathyroidism
Hyperthyroidism
Hypogonadism in young women and in men
Cyclosporine (?)
Heparin
Low turnover - decreased bone formation more pronounced than decreased bone
resorption
Liver disease - primarily primary biliary cirrhosis
Heparin
Age above 50 years
Increased bone resorption and decreased bone formation
Glucocorticoids
DPD excretion in osteoporosis
Increased urinary deoxypyridinoline excretion in osteoporosis
Values for urinary excretion of deoxypyridinoline (DPD), relative to
creatinine, in age-matched normal women (Group 1), women with
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osteoporosis or previous fractures (Group 2), and women with severe
osteoporosis (Group 3). Although there was overlap, urinary DPD excretion
was higher in the women with osteoporosis, especially those with severe
disease. Data from McLaren, AM, Hordon, LD, Bird, HA, Robins, SP, Ann
Rheum Dis 1992; 51:648.
Osteocalcin in osteoporosis
Serum osteocalcin in osteoporosis
Relationships in old women between the serum osteocalcin concentration
and age-adjusted Z scores for radius bone mineral density (BMD). A given
serum osteocalcin concentration was associated with BMD that ranged from
low to high and was therefore of limited diagnostic utility.
Osteocalcin predicts bone loss
Serum osteocalcin predicts bone loss
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Correlation between the initial serum osteocalcin concentration and the
change after two years in forearm bone mineral content (BMC, expressed as
a percent of the initial value) in postmenopausal women. Higher serum
osteocalcin values were predictive of a greater rate of bone loss. Data from
Johansen, JS, Riis, BJ, Delmas, PD, Christiansen, C, Eur J Clin Invest 1988;
18:191.
Bone markers risk hip fracture
Interaction of low bone mineral density and increased bone
turnover in predicting fracture risk
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In women over age 75 years followed prospectively, the odds ratio for hip
fracture was increased 2.7-fold in those with a 1 standard deviation
reduction in hip bone mineral density (BMD) but normal markers for bone
turnover (first column), approximately 2-fold in those with normal BMD but a
value for urinary C-terminal collagen crosslink excretion (CTX) or free
deoxypyridinoline excretion (D/Pyr) above the premenopausal range (second
and third columns), and 4.5-fold when both risk factors were present (last
two columns). Data from Garnero, P, et al, J Bone Miner Res 1996; 11:1531.
Bone turnover sCT response
Bone turnover and response to calcitonin
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Percent change in bone mineral content (BMC) of the lumbar spine in
relation to bone turnover in a group of postmenopausal women with
osteoporosis treated with salmon calcitonin for one year. Patients in the high
turnover group had higher baseline serum osteocalcin concentrations (11.6
versus 6.5 ng/mL) and urinary hydroxyproline excretion (30.4 versus 16.3
mg/g creatinine) and had an increase in BMC with calcitonin. In comparison,
BMC was stable in patients with normal bone turnover. No such relationship
could be demonstrated at the femoral diaphysis. Data from Civitelli, R,
Gonnelli, S, Zacchei, F, et al, J Clin Invest 1988; 82:1268.
Calcium versus estrogen on bone
Methods to slow bone loss in postmenopausal women
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Effects of three interventions on distal forearm bone density in postmenopausal
women with low baseline forearm bone density. Bone loss was significantly slowed
or prevented with either exercise plus estrogen or exercise plus calcium
supplementation. The former regimen was both more effective and associated with
a higher incidence of side effects, such as breast tenderness and vaginal bleeding.
Data from Prince, RL, Smith, M, Dick, IM, et al, N Engl J Med 1991; 325:1189.
Alendronate dose osteoporosis
Alendronate dose response in osteoporosis
Mean changes in bone mineral density (measured by dual-energy x-ray absorptiometry) in the
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lumbar spine and femoral neck in postmenopausal women with osteoporosis treated with placebo
or different doses of alendronate for three years. Alendronate caused an increase in bone density,
an effect that was most pronounced at a dose of 10 mg/day (red squares). Bone density fell in
the placebo group. Data from Liberman, UA, Weiss, SR, Broll, J, et al, N Engl J Med 1995;
333:1437.
Bone loss despite estrogen
Continued bone loss in some women treated with estrogen
Distribution of percent rate of change in bone mineral density (BMD) per year in the lumbar
spine (left) and femoral neck (right) in postmenopausal women who were untreated or
treated with estrogen. Almost all untreated women lost bone in the spine and most lost bone
at the femoral neck. Estrogen therapy had an overall benefit but some women continued to
lose bone. Data from Cosman, F, Nieves, J, Wilkinson, C, et al, Calcif Tissue Int 1996;
58:236.
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risedronate markers fracture
Risedronate: bone markers correlate with fracture rates
In the risedronate vertebral fracture trials, reductions in urinary CTX and
NTX with risedronate therapy (5 mg/day for three years) were significantly
associated with reductions in vertebral fracture rates over one year and over
three years. The placebo group is represented by the red broken lines and
the risedronate 5 mg group by the blue solid lines. All patients received
calcium supplementation (1000 mg/day) and vitamin D (if levels were low).
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Data from Eastell, R, Barton, I, Hennon, RA, et al. Relationship of early
changes in bone resorption to the reduction in fracture risk with risedronate.
J Bone Miner Res 2003; 18:1051.
NTX Ca supplementation
Urinary N-telopeptide excretion predicts response to calcium
supplementation
Women receiving calcium supplementation who were in the highest quartile
(Q4) of urinary N-telopeptide (NTX) at baseline had a significantly greater
decrease in spine bone mineral density (BMD) over the course of one year
than subjects with the lowest baseline NTX values (Q1).
Ns: not statistically significant from baseline BMD.
* p <0.05.
p <0.001.
Data from Rosen, CJ, Chesnut III, CH, Mallinak, NJ, J Clin Endocrinol Metab
1997; 82:1904.
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