Journal of Clinical Densitometry: Assessment & Management of Musculoskeletal Health, vol. 20, no.

3, 346–352, 2017
© 2017 The International Society for Clinical Densitometry.
1094-6950/20:346–352/$36.00
http://dx.doi.org/10.1016/j.jocd.2017.06.020

Original Article

Bone Turnover Markers: Use in Fracture Prediction

Tatiane Vilaca, Fatma Gossiel, and Richard Eastell*
Academic Unit of Bone Metabolism, University of Sheffield, Sheffield, UK

Abstract
Bone turnover markers (BTMs) provide us with a noninvasive approach to studying bone turnover and
they can be measured easily and with good precision, especially using automated analyzers. BTMs increase
at menopause, and these higher levels are associated with more rapid bone loss. In some but not all studies,
they are also associated with greater risk of fracture. However, the evidence base for use as predictors of frac-
ture is not robust, and so BTMs have not been included in fracture prediction models. Further research is
needed, and this might include (1) use of reference analytes such as C-telopeptide of type I collagen and
procollagen I N-propeptide, measured using automated analyzers in subjects in the fasting state on more than
1 occasion; (2) careful collection of vertebral fractures, which would be the primary endpoint; and (3) common
approach to statistical analyses with results expressed as hazard ratio per standard deviation of increase in
BTM. We believe that by improving our approach to studying the relationship between BTMs and fracture
risk, any association will become clearer and that in the future we might then be able to include BTMs in
our fracture prediction models.

Key Words: Bone resorption; bone turnover markers; fracture; osteocalcin; osteoporosis.

Introduction
The current approaches for predicting who might
fracture are based on the measurement of bone mineral
density and the inclusion in risk calculators of certain
clinical risk factors. Such risk calculators include FRAX,
QFRACTURE, and the Garvan calculator. Bone turn-
over markers (BTMs) have been considered for use in such
calculators, but have not yet been accepted (1). The article
will discuss the rationale for using BTMs for the predic-
tion of fracture and the evidence base and considers the
research agenda needed to allow acceptance.
Rationale
At menopause, there is acceleration in the rate of bone
loss from the spine and hip, and this is related to the in-
crease in bone turnover.The bone resorption marker urinary
N-telopeptide of type I collagen (NTX) increases about 2
*Address correspondence to: Richard Eastell, MD, FRCP,
FRCPath, FMedSci, Metabolic Bone Centre, Northern General
Hospital, Herries Road, Sheffield, South Yorkshire, S5 7AU, UK.
E-mail: r.eastell@sheffield.ac.uk
years before the last menstrual period, peaks about 1 year
after the last menstrual period, and thereafter remains about
20% above the premenopausal level (2), and this eleva-
tion remains for several decades after the menopause (3)
(Os des Femmes de Lyon cohort). Those women who had
an NTX above the medial value had a greater rate of bone
loss from the spine and hip and also a greater risk of frac-
ture (4). These associations were independent of bone
mineral density.
Postmenopausal bone loss is caused by an increase in
the overall rate of bone turnover, or the activation fre-
quency (in bone histomorphometry parlance), and a
negative imbalance between bone resorption and bone
formation. Bone formation is coupled to bone resorp-
tion, and so there is also an increase in bone formation
markers at menopause. Bone loss is more rapid in women
who have the highest BTMs and the greatest imbalance
between resorption and bone formation (5).
Thus, 1 mechanism for higher rate of turnover predis-
posing to fracture might be the greater propensity for
low bone mineral density in the long term. However, high
bone turnover may affect bone strength independent of
bone mineral density. These effects may be particularly
marked in cancellous bones, such as the vertebrae. One

346

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BTM and Fracture Prediction
mechanism relates to stress risers. If resorption cavities
appear on opposite sides of a trabeculum, then this can act
as a weak point that is subject to fracture, a stress riser (6).
High turnover is associated with the presence of more newly
formed bone; such bone has not completed its secondary
mineralization (7) and has less complete cross-linking as
compared with mature bone (8,9).
The Tools
We can assess bone turnover using bone biopsy, but
this would never be suitable for studying the relationship
between bone turnover and fracture risk as the proce-
dure is invasive. However, BTMs have been validated
against bone histomorphometry and the other gold stan-
dard technique, radiotracer kinetics, and shown to corre-
late well with bone turnover at baseline and after therapy
(10,11).
The BTMs reflect the activity or the number of the os-
teoclasts (bone resorption) and the work activity of the os-
teoblasts (bone formation markers). These are listed in
Table 1. Those markers that reflect the activity of the
osteoclasts include the pyridinium crosslink (e.g.,
deoxypyridinoline), a crosslink bound to the N (NTX) or
C (CTX) telopeptide of type I collagen; CTX can include
an octapeptide sequence (CTX-I) or a longer sequence that
is cleaved by cathepsin K (C-terminal cross-linking
telopeptide of type I collagen generated by matrix
metalloprotease or ICTP). Type I collagen is found in many
other tissues, but its turnover in bone is greater than in other
tissues in health. The bone formation markers are all pro-
teins that are produced by the osteoblast. Osteocalcin is
produced only by osteoblasts and odontoblasts, and so is
specific to bone.
There are other biochemical analytes that relate to bone.
Some of these are regulators of bone turnover such as those
Table 1
Bone Turnover Markers in Common Use
Bone formation
Osteocalcin (OC)
Bone alkaline phosphatase (bone ALP)
Procollagen I N-propeptide (PINP)
Procollagen I C-propeptide (PICP)
Bone resorption
C-terminal cross-linking telopeptides of type I collagen
(CTX-I)
N-terminal cross-linking telopeptides of type I
collagen (NTX-I)
C-terminal cross-linking telopeptide of type I collagen
generated by matrix metalloproteinases (CTX-MMP,
ICTP)
Deoxypyridinoline (DPD)
Tartrate-resistant acid phosphatase, type 5b
(TRACP5b)
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347
controlling bone resorption (receptor activator of nuclear
factor κB ligand and osteoprotegerin) and those control-
ling bone formation (sclerostin and Dkk-1). There are
markers that may relate to collagen aging (the alpha and
beta forms of CTX-I). There are markers that relate to the
glycosylation of type I collagen and that are higher in dia-
betes, such as pentosidine.This review will not consider these
related analytes.
The Findings
In most of the studies in women, one of the BTMs was
associated with an increase in fracture risk (Table 2). Indeed,
in several of the studies, the predictive ability of an in-
crease in BTMs was independent of bone mineral density
(15–18,27,29,35).
It has been proposed that the reference BTMs could be
serum CTX-I for resorption and procollagen 1 N-propeptide
(PINP) for formation. A meta-analysis has been com-
pleted for serum CTX-I and PINP in 10 prospective cohort
studies of untreated individuals. It reported that for a 1 stan-
dard deviation (SD) increase, the risk of all fractures was
1.18 with CTX and 1.23 with PINP. These results were not
adjusted for bone mineral density.
How could these results be included in a fracture risk
prediction tool? Johnell and colleagues (36) proposed that
urinary CTX might be used in combination with other risk
factors such as low bone mineral density to predict hip frac-
ture. However, one of the challenges of that analysis was
the small number or people who have a high CTX and low
BMD and so are at higher risk of fracture.
The results of the studies in men are less clear. In the
Montceau les Mines Osteoporosis study, there was no pre-
dictive value. In the Osteoporosis in Men study, there was
predictive value of CTX-I and PINP for hip and non-
spine fracture, but not after adjustment for bone mineral
density. In the Dubbo study, there was predictive value for
CTX-MMP (ICTP) for osteoporosis-related fractures (28).
In a study from Western Australia, serum osteocalcin, but
not CTX or PINP, was associated with hip fracture (34).
The Challenges
The studies on fracture and BTM have been summa-
rized (12), and there are a number of challenges that are
apparent.
(1) The studies have used a number of BTMs. Although
the bone resorption markers have usually appeared
more promising, it is the bone formation markers that
have been more commonly studied (Fig. 1A). This
is one of the reasons the International Osteoporo-
sis Foundation/International Federation of Clinical
Chemistry and Laboratory Medicine working group
proposed that we have reference markers that should
be included in all studies, such as serum CTX and
PINP so that all studies have at least a common
denominator.
Volume 20, 2017
348 Vilaca, Gossiel, and Eastell

Table 2
The Association Between BTM and Fracture Risk, Given as a Relative Risk, Based on Vasikaran et al (12) and
Morris et al (13)

Author, year Frac site Metric BTM RR CI

Szulc, 1993 (14) Hip >2 SD premenopausal women sun-OC 5.9 (1.5–22.7)
Akesson, 1995 (15) All OR/SD change in BTM s-OC no RR
Garnero, 1996 (16) Hip >2 SD premenopausal women s-OC 1 (0.6–1.6)
s-BALP 1.1 (0.7–1.7)
uNTX 1.4 (0.9–2.2)
Hip OR for 1 SD increase in BTM s-OC 1 (0.8–1.2)
and 1 SD decrease in BMD s-BALP 0.9 (0.7–1.2)
uNTX 1.1 (0.9–1.4)
Hip Highest Q × Lowest Q s-OC 1.1 (0.7–1.9)
s-BALP 0.9 (0.6–1.4)
uNTX 1.1 (0.7–1.9)
Vergnaud, 1997 (17) Hip Highest quartile × Q2-4 s-OC 1.3 (0.7–2.1)
Ross, 2000 (18) All OR/SD change in BTM s-BALP 1.53 (1.18–1.98)
Vertebral OR/SD change in BTM s-BALP 1.54 (1.12–2.12)
Nonvertebral OR/SD change in BTM s-BALP 1.88 (1.34–2.65)
Chapurlat, 2000 (19) Hip >2 SD premenopausal range s-CTX 1.86 (1.01–3.76)
Luukinen, 2000 (20) All cases × controls Z-score > 1 SD s-OC 1.22 (0.68–2.17)
Garnero, 2000 (21) All >2 SD premenopausal range s-OC 1.5 (0.8–2.7)
s-BALP 1.9 (1.13–3.4)
s-CTX 1.9 (1.05–3.6)
u-NTX 1.7 (0.9–3.2)
s-PINP 1.6 (0.8–3.4)
Garnero, 2000 (21) All Highest vs lowest quartiles s-OC 1.5 (0.8–2.7)
s-BALP 2.4 (1.3–4.2)
s-CTX 2.1 (1.2–3.8)
u-NTX 1.7 (0.9–3.2)
s-PINP 1.3 (0.7–2.4)
Tromp, 2000 (22) All Highest quartile × Q2-4 u-NTX 1.9 (0.8–4.6)
Nonvertebral Highest quartile × Q2-4 u-NTX 2.6 (1.3–5.0)
Hip Highest quartile × Q2-4 u-NTX 2.6 (0.8–8.1)
Greenfield, 2001 (23) Nonvertebral Cases × controls in upper quartile u-NTX no RR
Vertebral Cases × controls in upper quartile u-NTX 1.2 (1.0–1.5)
All Cases × controls in upper quartile s-OC no RR
Bauer, 2001 (24) Hip Lowest quintile × others s-OC no RR
s-BALP no RR
s-CTX no RR
Bauer, 2001 (24) Vertebral Highest quintiles × others s-OC no RR
s-BALP no RR
s-CTX no RR
Bruyere, 2003 (25) Vertebral Highest vs lowest quartiles s-OC 1.12 (0.62–2.04)
s-BALP 0.66 (0.37–1.17)
Melton, 2003 (26) All OR/SD change in BTM s-OC 0.92 (0.78–1.1)
Vertebral OR/SD change in BTM s-OC 0.8 (0.65–0.98)
Hip OR/SD change in BTM s-OC 1.16 (0.75–1.81)
(Continued)

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BTM and Fracture Prediction 349

Table 2 (Continued)

Author, year Frac site Metric BTM RR CI

Gerdhem, 2004 (27) All Highest quartile × Q2-4 s-OC 1.19 (0.83–1.72)
s-BALP 0.89 (0.61–1.29)
s-CTX 1.18 (0.81–1.7)
Hip Highest quartile × Q2-4 s-OC 0.77 (0.35–1.71)
s-BALP 0.94 (0.46–1.93)
s-CTX 1.01 (0.48–2.11)
Vertebral Highest quartile × Q2-4 s-OC 1.41 (0.75–2.64)
s-BALP 1.43 (0.78–2.71)
s-CTX 1.94 (1.05–3.58)
Meier, 2005 (28) All Highest vs lowest quartiles s-CTX 1.6 (0.8–3.3)
s-PINP 1.4 (0.8–1.6)
OR/SD change in BTM s-CTX 1.2 (0.98–1.6)
s-PINP 1.1 (0.9–1.4)
Sornay-Rendu, 2005 (29) All Highest quartile × Q2-4 s-BALP 2.2 (0.4–3.8)
Dobnig, 2007 (30) Hip Per increment of 1 of the s-OC 0.99 (0.97–1.0)
respective unit
s-CTX 1.27 (0.45–3.6)
Nonvertebral Per increment of 1 of the s-OC 0.99 (0.99–1.0)
respective unit
s-CTX 1.41 (0.77–2.6)
Szulc, 2008 (31) All OR/SD change in BTM s-OC no RR
s-BALP no RR
s-CTX no RR
s-PINP no RR
Bauer, 2009 (32) Hip Highest quartile × Q2-4 s-CTX 1.76 (1.04–2.98)
s-PINP 2.13 (1.23–3.68)
Nonvertebral Highest quartile × Q2-4 s-CTX 1.29 (0.99–1.69)
s-PINP 1.57 (1.21–2.05)
Ivaska, 2010 (33) All OR/SD change in BTM s-CTX 1.13 (1.01–1.27)
Highest tertile × lowest s-CTX 1.29 (0.99–1.67)
Vertebral OR/SD change in BTM s-CTX 1.32 (1.05–1.67)
Highest tertile × lowest s-CTX 1.42 (0.88–2.38)
Chubb, 2015 (34) Hip OR/SD change in BTM s-OC 1.20 (1.00–1.42)
s-PINP no RR
s-CTX no RR
Abbr: BTM, bone turnover marker.

(2) Most studies had all fractures or hip fractures as the
main endpoint (Fig. 1); only 3 studies included spine
fracture as the endpoint (Fig. 1B), yet from theoreti-
cal grounds, it would be expected that spine fracture
would be more strongly related to high levels of bone
turnover (e.g., treatments that reduce bone turnover
result in the greatest reductions in vertebral frac-
ture; also, high bone turnover during pregnancy pre-
disposes to vertebral but not usually other fractures).
(3) It is very difficult to combine studies in an analysis.
This is because each study reports the results in
different ways. Some define high bone turnover as
being more than 1 or 2 SDs above the mean or in
the highest tertile, quartile, or quintile (Fig. 1B). Fur-
thermore, these high turnover groups are then com-
pared with either the rest of the group or the lower
group. Johansson et al (37) used a mathematical ap-
proximation to give all results in hazard ratio of
fracture per SD increase in BTM.
(4) Although most studies report a positive associa-
tion between BTM and fracture risk, each study has
several BTM and may have several fracture end-
points, so these could be false positives. It would be
better to define the reference analytes CTX and PINP
as the primary analysis along with single fracture type.
(5) The concern about false positives is reinforced by
the inconsistency of results. Thus, for osteocalcin, the
association with fracture might be strong (14,25), or
moderate (17,26), borderline (15,16), or nonsignificant
(20,21,23,27,30,38).

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350 Vilaca, Gossiel, and Eastell

thing in the morning after an overnight fast.

Paradoxically, the 1 study that compared the CTX
in the morning and in the afternoon found that it was
the afternoon sample that was associated with frac-
ture risk (19).

Future Directions
Better studies need to be designed to clarify any asso-
ciation between BTM and fracture risk.
(1) The research questions need to be clearly estab-
lished, making key markers (such as CTX and PINP)
the primary endpoint; also, the fracture site should
be defined. These markers need to be standardized
so that different manufacturers’ assays provide the
same result. The duration should be considered
carefully as BTM may better predict fracture in the
short term (20,33).
(2) The population of interest should be selected and pro-
spectively followed, and the BTMs should be col-
lected under ideal conditions. Many different
international centers should be involved. It is also rec-
ommended that the studies involve multiple mea-
surements of BTM during the follow-up (33).
(3) Data should be analyzed in consistent ways, for
example, express the hazard ratio per SD increase
in BTM. This will allow meta-analysis of results. Data
should also be adjusted for bone mineral density and
clinical risk factors so that the BTM are evaluated
Fig. 1. (A) Types of BTM reported in different studies
for their value in fracture risk prediction algorithms.
(12). If a study reported more than 1 marker or more than
BMD is usually negatively associated with age,
1 metric, each 1 was counted separately. For this reason,
especially in older people (3,39–41).
the total number of studies in the histogram is greater than
(4) It is important to consider the balance between bone
the number of studies published. (B) The type of statisti-
resorption and bone formation as this might be just
cal comparisons used in the studies by fracture site.
as important as the rate of bone turnover for pre-
1, >2 SD premenopausal range;
dicting fracture risk. Different approaches have been
2, 1 SD increase in BTM + 1 SD decrease in BMD;
used to compare these 2 types of markers, such as
3, SD/OR change in BTM;
using an SD approach (42), a multiple of medians ap-
4, 1 UI increase in the respective unit;
proach (43), or a regression approach (5).
5, 3 highest quartiles x lowest quartile;
(5) The issues raised so far relate to groups of
6, Highest × lowest quartiles;
individuals. However, when we apply the results to
7, Highest × 3 lower quartiles;
the individual, other issues are important to the clini-
8, Cases × controls (upper quartile);
cal utility of BTMs. The BTMs vary from day to day,
9, Lowest quintile × other quintiles;
and this is particularly marked for those markers
10, Highest tertile × lowest tertile;
that are measured in the urine. This variability can
11, Highest quintile × other quintiles;
be captured by the “least significant change”; this
12, cases × controls Z score> 1 SD.
value was just 31% for bone alkaline phosphatase,
but it was 67% for urinary NTX (44). BTMs are
(6) There was also inconsistency by the type of assay; higher in the year after a fracture, and they can also
thus free deoxypyridinoline can be measured in the be higher in patients with chronic kidney disease,
urine by immunoassay or by high-performance liquid especially those markers that are excreted by
chromatography. The association with fracture risk the kidney such as serum CTX and osteocalcin.
was significant for the immunoassay but not for the Finally, there have been a flurry of recent publica-
high-performance liquid chromatography assay (35). tions of reference ranges for BTMs (13), but the
(7) It is generally recommended that the bone resorp- manufacturer’s reference intervals are not always
tion markers are measured on samples taken first so reliable.

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BTM and Fracture Prediction
Thus, BTMs hold promise as an independent predictor
for fracture. However, before they can be used for this
purpose in clinical practice, we need further carefully con-
ducted prospective studies that make the collections for the
markers in the correct conditions (fasting state, stored at
−80°C), include at least those markers recommended as ref-
erence standards (CTX and PINP), and are analyzed in a
standard manner (such as relative risk per SD increase).
Acknowledgments
Tatiane Vilaca is funded by Conselho Nacional de
Desenvolvimento Científico e Tecnológico (CNPq), Brazil.
Richard Eastell is a Senior Investigator with the National
Institute of Health Research.
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