Journal of Bone and Mineral Metabolism (2021) 39:237–244

https://doi.org/10.1007/s00774-020-01140-y

ORIGINAL ARTICLE

Changes of bone turnover markers after elderly hip fracture surgery

Xin‑ping Li1 · Xiao‑yu Li1 · Ming‑hui Yang2 · Shi‑wen Zhu2 · Xin‑bao Wu2 · Ping Zhang1

Received: 28 June 2020 / Accepted: 7 August 2020 / Published online: 2 September 2020
© The Japanese Society Bone and Mineral Research and Springer Japan KK, part of Springer Nature 2020

Abstract
Introduction Bone turnover markers (BTMs) can be used to monitor bone metabolism, while the actual clinical changing
in hip fracture had not been certified to evaluate the changes of BTMs during the healing process after surgery of elderly hip
fractures; and to get the effects of operation type, gender, serum 25(OH)D level, and age on bone turnover markers.
Materials and methods A total of 100 elderly cases with hip fracture were selected, including 74 females and 26 males,
and the patients were followed to 180–230 days after surgery. Serum levels of N-propeptide of type 1 collagen (P1NP),
C-terminal crosslinking telopeptides of type 1 collagen (CTX), Osteocalcin (OC), and 25 hydroxy vitamin D (25OHD) were
investigated. Bone mineral density (BMD) was measured with dual-energy X-ray absorptiometry (DXA).
Results (1) P1NP and CTX showed peak time at 30–60 days after operation, while OC keep going even at 180–230 days;
P1NP showed less than 4 times elevation during healing, CTX and OC only had less than 2 times rise. (2) Female had
higher serum CTX and OC than male, intramedullary nailing for intertrochanteric fracture patients had higher P1NP than
hip replacement for femoral neck fracture patients, and both the degrees of increase were less than 50%. (3) Serum average
25(OH)D level had no effect on BTMs during the fracture healing; different from the young old (65–84 years), serum OC
level of eldest older patients(≥ 85 years) decreased early in the process of fracture healing.
Conclusions BTMs reached the peak level in 30–60 days after surgery, P1NP showed less than 4 times elevation, and CTX
and OC had less than 2 times rise. It was not necessary to take gender into account when observing P1NP, and it was not
necessary to take fracture and operation type into account when observing CTX and OC.

Keywords Osteoporosis · Hip fracture · Bone turnover markers · Fracture healing

Introduction
We can observe the process of fracture healing from mani-
festations of imaging, and understand the process from the
alternation of bone turnover markers (BTMs). BTMs are
derived from both cortical and trabecular bone; they reflect
the metabolic activity of the entire skeleton rather than that
of individual cells or the process of mineralization. BTMs
vary throughout the course of fracture repair with their rates
of change being dependent on the size of the fracture and
* Ping Zhang
13611216601@163.com
1
Department of Geriatrics, Beijing Jishuitan Hospital,
the Fourth Medical College of Peking University,
Beijing 100035, China
2
Department of Trauma Orthopaedics, Beijing Jishuitan
Hospital, the Fourth Medical College of Peking University,
Beijing 100035, China
the time that it will take to heal, and it has large potential
as an additional non-invasive diagnostic feature in the treat-
ment of fracture healing [1–7]. The stable markers of bone
formation are N-propeptide of type 1 collagen (P1NP), the
commonly used and stable bone resorption marker in clinic
is C-terminal crosslinking telopeptides of type 1 collagen
(CTX), and Osteocalcin (OC) produced at the end of osteo-
blast maturation and related to mineralization.
Hip fracture is one of the most common end events in
elderly osteoporosis patients. According to the International
Osteoporosis Organization, the number of hip fractures in
the world will reach 6.26 million by 2050 [8], of which
Asia will account for more than 50%. However, we do not
have enough data on the change of BTMs during the frac-
ture healing. For these data, it was obtained from younger
samples [1, 9–12], consisted of heterogeneous fractures [9,
13, 14], and had lower sample sizes [9, 15], reducing their
generalizability to hip fractures in the elderly.

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And hip fractures have healing trajectories distinct from
long bone fractures; for metaphyseal bone involvement and
lower weight-bearing status during recovery, it is likely that
these differences could cause distinct changes in BTMs after
hip fracture from other location of fractures. Therefore, this
paper is to explore the normal changes of BTMs (serum
25(OH)D, CTX,P1NP, and OC) in the process of postopera-
tive healing of elderly hip fracture, and further deepen the
understanding of the physiological and biochemical changes
of bone metabolism.
Materials and methods
This study is a prospective observation study. Apart from
rehabilitation exercise, adequate calcium and vitamin D sup-
plementation, calcitonin in 1 month after fracture, there are
no other intervention measures.
Study participants
All 100 patients were 65 or older who hospitalized and
had hip fracture operation from June 2016 to June 2017;
all of them were fragility fractures; operation were com-
pleted within 1 week from fracture. All the patients had
completed dual-energy X-ray absorptiometry (DXA) (GE
lunar, Madison, WI, USA) before operation. Serum cal-
cium, phosphorus, 25(OH)D, P1NP, CTX, and OC were
measured before operation (the operation was done within
1 week after fracture) and 30–60 days, 80–120 days, and
180–230 days after operation. All patients were given reha-
bilitation guidance and exercise as early as possible, and all
the patients recovered from the fracture smoothly. Exclusion
criteria: violent fractures, and/or patients who have received
bisphosphonates, calcitriol, alfacalcidol, calcitonin, estro-
gen and estrogen receptor modulators, and other drugs that
affect bone metabolism before surgery, patients who have
received bisphosphonates and/or teriparatide and/or estrogen
receptor modulators after surgery; patients with secondary
osteoporosis, including hypoparathyroidism or hyperpar-
athyroidism, Cushing’s syndrome; chronic liver disease and
chronic kidney disease; rheumatism or rheumatoid arthri-
tis; gastric ulcer, Crohn’s disease, segmental enteritis, and
chronic dysentery in recent 2 years; neuromuscular diseases
with non genetic influence on bone density; patients with
skin diseases unable to receive sunlight, non-union (US
FDA: 9 months elapsed time with no healing progress for
3 months [16]), delayed healing (union achieved within from
3 to 12 months [17]) or osteonecrosis, etc. These data were
obtained from Jishuitan Hospital. The study was approved
by the ethics review committee of Beijing Jishuitan Hospital,
with the approval number of 202002-04.
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Journal of Bone and Mineral Metabolism (2021) 39:237–244
Blood samples
All patients registered fracture time and specimen collec-
tion time; all subjects collected 3 ml of fasting blood in
the morning, using vacuum vessel with separation glue,
the serum was centrifuged at low temperature and stored
at − 20 °C to avoid repeated freezing and thawing of sam-
ples, and the samples were been analyzed less than 24 h.
The levels of P1NP, CTX, OC, and 25(OH)D in serum
were quantitatively determined using Cobas kit of Roche
company(Shanghai). The sensitivity was less than 5.00 ng/
ml, 0.07 ng/ml, 0.05 ng/ml, and 3.00 ng/ml, respectively.
The coefficients of variation between batches and within
batches were less than 10%.
Statistical methods
Using IBM SPSS 19 statistical software, the continuous
variables were expressed as mean ± standard deviation. In
the operation group, only the Hip replacement for femoral
neck fractures group and intramedullary nailing for inter-
trochanteric fractures group were analyzed, because the
case of the internal fixation of the femoral neck group and
dynamic hip screw group was small.
The longitudinal BTMs data were analyzed using gen-
eralized estimating equation with each patents uniquely
coded as a random effect; Time was coded as a cat-
egorical variable (baseline, 30–60 days, 80–120 days,
180–230 days); CTX, P1NP, and OC as dependent vari-
ables separately; gender and operative method as fixed
effects; age, body mass index, serum calcium, serum
phosphorus level, albumin, hemoglobin, and bone min-
eral density of hip and serum 25(OH)D level as covariant
quantities.
Results
Sample characteristics and follow‑up
Among 100 elderly patients with fracture, 74 females and
26 males; 33 were intertrochanteric fracture, 67 were femo-
ral neck fracture; 30 were intramedullary nailing, 57 were
total hip or hemi hip arthroplasty, 9 were hollow screw
internal fixation, 4 were dynamic hip screw internal fixa-
tion; all patients were 65–92 (77.2 ± 6.3) years old, BMI
was 23.2(± 3.5) kg/m2, average lumbar BMD in DXA was
0.91(± 0.19) g/cm2; average BMD of the opposite hip was
0.69 (± 0.12) g/cm2. Serum 25(OH)D levels ranged from 3.0
to 42.3 ng/ml, with a mean of 15.4 ng/ml at baseline, and
58% patients were vitamin D deficiency(< 20 ng/ml).
Journal of Bone and Mineral Metabolism (2021) 39:237–244 239

The operation was done within 1 week (3.9 ± 2.5 days)

BMI: body mass index; Ca: calcium corrected by albumin level; P: phosphatase; ALB: albumin; HGB: hemoglobin; BUN: blood urea nitrogen; Cr: blood creatinine; Hip-BMD: bone mineral
density for hip; p value: t test p value between the same sex; p value between hip replacement: t test p value between the male and female hip replacement surgery; p value between intramedul-
0.67 ± 0.09
0.61 ± 0.11

0.80 ± 0.07
0.78 ± 0.09

0.73 ± 0.13
Hip-BMD
after fracture, the first follow-up time was 30–60 (46.6 ± 6.0)

0.027

0.633

0.000
0.000
days after surgery, 98 patients completed the follow-up;
the second was 80–120 (98.2 ± 10.8) days, 99 patients
completed; the third was 180–230 (191.2 ± 18.8) days, 92

59.2 ± 13.2
56.2 ± 14.9

76.7 ± 14.2
83.9 ± 17.8

57.9 ± 13.1
Cr, umol/l
patients completed. See Table 1 for details of the patients.

0.417

0.301

0.025
0.000
P1NP

BUN, mmol/l
The change of P1NP after operation was significantly

6.7 ± 1.8
6.8 ± 1.4

7.0 ± 1.9
8.3 ± 2.3

5.5 ± 1.3
0.766
increased from baseline (p < 0.001). The mean baseline

0.146

0.000
0.085
serum P1NP level was 40.6 ng/ml and ranged from 9.0 ng/
ml to 101.9 ng/ml. Serum P1NP levels increased in 291%

123.1 ± 10.4
110.4 ± 15.4

138.3 ± 10.1
112.6 ± 10.7

130.1 ± 15.8
percent (25–75%: 220–456%; p < 0.001) from baseline to

HGB, g/l
30–60 days, and then increased in 228% percent (25–75%:

0.002

0.000

0.000
0.646
184–335%; p < 0.001) from baseline at 80–120 days and
increased in 159% percent (25–75%: 113–229%; p = 0.009)
from baseline at 180–230 days postoperatives.

42.7 ± 3.1
40.5 ± 3.3

42.4 ± 2.6
41.1 ± 2.9

44.0 ± 3.6
ALB, g/l
There was no gender difference in the analysis of P1NP of

0.013

0.268

0.799
0.634
hip fracture patients over 65 years old included in this paper
(p = 0.829); There was also no significant difference between
gender in the hip replacement for femoral neck fractures

0.91 ± 0.17
0.98 ± 0.17

0.84 ± 0.18
0.82 ± 0.15

0.79 ± 0.16
P, mmol/l
group (p = 0.266) and intramedullary nailing for intertro-

0.164

0.769

0.188
0.016
chanteric fracture group (p = 0.801). Intramedullary nailing
group has higher serum P1NP level than hip replacement
group (p = 0.019)(Table 2, Fig. 1). There was no associa-
Ca, mmol/l

2.36 ± 0.17
2.28 ± 0.11

2.33 ± 0.06
2.24 ± 0.06

2.34 ± 0.10
tion between serum 25(OH)D deficiency (< 20 ng/ml) and 0.055

0.005

0.572
0.358
serum P1NP levels (p = 0.230). There was also no associa-
tion between oldest old patients (≥ 85 years old) and serum

lary nailing: t test p value between the male and female intramedullary nailing surgery
P1NP levels (p = 0.953).
BMI, kg/m2

22.5 ± 3.0
24.5 ± 5.4

23.1 ± 2.5
24.1 ± 3.5

22.7 ± 2.2
0.146

0.463

0.575
CTX 0.810

The increase of serum CTX level was lower than that of

Age, years

77.4 ± 6.1
80.7 ± 4.7

73.0 ± 4.9
79.4 ± 6.6

73.0 ± 6.8

P1NP, but still significant (p < 0.001) compared with base-

0.033

0.016

0.025
0.537

line. The mean baseline serum CTX level was 0.53 ng/ml
and ranged from 0.08 ng/ml to 1.08 ng/ml. Serum CTX
levels increased in 147% (25–75%: 99–201%; p < 0.001)
Cases
Table 1  General condition of hip fracture patients

from baseline to 30–60 days after surgery, and then stayed

45
20

12
10

13

at 113% (25–75%: 86–159%; p = 0.635) from baseline at

80–120 days and 108% (25–75%: 83–138%; p = 0.149) from
Intramedullary nailing

Intramedullary nailing

p value between intramedullary nailing

baseline at 180–230 days postoperatives.

Hip replacement

Hip replacement

Female had higher serum CTX level than male in hip

p value between hip replacement

fracture patients over 65 years old included in this paper

(p = 0.038). There was no difference in serum CTX level
Surgery

p value

p value

between hip replacement group and intramedullary nailing

group (p = 0.174) (Table 2, Fig. 2). There was no association
between 25(OH)D deficiency (< 20 ng/ml) and serum CTX
levels (p = 0.110) (Fig. 4a). And, there was no association
Gender

Female

between oldest old patients (≥ 85 years old) and serum CTX

Others
Male

levels (p = 0.959).

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Table 2  Bone turnover marker lever of hip fracture patients before and after surgery
Gender Surgery Cases Before surgery 30–60 days after surgery 80–120 days after surgery 180–230 days after surgery

P1NP, ng/ CTX, ng/ml OC, ng/ml P1NP, ng/ml CTX, ng/ml OC, ng/ml P1NP, ng/ CTX, ng/ OC, ng/ml P1NPng/ml CTXng/ml OCng/ml
ml ml ml

Female Hip 45 39.8 ± 18.9 0.60 ± 0.26 14.0 ± 7.7 111.9 ± 33.1 0.77 ± 0.24 21.0 ± 7.0 88.6 ± 28.6 0.62 ± 0.25 22.2 ± 7.3 57.5 ± 19.8 0.53 ± 0.24 20.4 ± 6.9
replace-
ment
Intramed- 20 40.5 ± 16.8 0.50 ± 0.29 14.3 ± 6.3 138.6 ± 57.7 0.83 ± 0.36 23.9 ± 8.8 99.0 ± 42.3 0.66 ± 0.27 25.3 ± 10.2 71.1 ± 35.9 0.57 ± 0.27 23.1 ± 7.3
ullary
nailing
p value 0.902 0.225 0.896 0.066 0.541 0.158 0.325 0.627 0.239 0.128 0.559 0.177
Male Hip 12 28.7 ± 5.2 0.30 ± 0.07 8.4 ± 1.1 110.6 ± 43.6 0.62 ± 0.18 18.4 ± 4.5 83.4 ± 19.8 0.44 ± 0.14 20.3 ± 3.8 52.8 ± 11.2 0.43 ± 0.16 18.8 ± 4.2
replace-
ment
Intramed- 10 33.9 ± 16.0 0.47 ± 0.26 11.7 ± 4.7 144.1 ± 46.4 0.65 ± 0.30 18.2 ± 5.6 95.0 ± 24.8 0.49 ± 0.29 19.1 ± 6.0 64.2 ± 26.9 0.48 ± 0.27 18.5 ± 5.5
ullary
nailing
p value 0.597 0.098 0.264 0.097 0.807 0.931 0.237 0.610 0.600 0.235 0.620 0.892
Others 13 41.1 ± 18.8 0.57 ± 0.21 12.8 ± 4.0 81.1 ± 38.7 0.72 ± 0.34 22.5 ± 6.2 70.0 ± 30.4 0.69 ± 0.34 24.2 ± 7.0 62.9 ± 31.0 0.57 ± 0.31 22.9 ± 8.6
p value for hip replace- 0.327 0.001 0.003 0.909 0.057 0.230 0.557 0.018 0.220 0.302 0.188 0.441
ment
p value for intramedul- 0.322 0.801 0.268 0.794 0.197 0.075 0.746 0.137 0.091 0.602 0.404 0.096
lary nailing

P1NP: N-propeptide of type 1 collagen; CTX:C-terminal crosslinking telopeptides of type 1 collagen; OC: osteocalcin; p value: t test p value between the same sex; p value between hip replace-
ment: t test p value between the male and female hip replacement surgery; p value between intramedullary nailing: t test p value between the male and female intramedullary nailing surgery
Journal of Bone and Mineral Metabolism (2021) 39:237–244
Journal of Bone and Mineral Metabolism (2021) 39:237–244 241

Fig. 1  Changes of P1NP before and after surgery in elderly hip fracture patients. a Trend of P1NP after hip fracture operation in different gen-
ders; b trend of P1NP after different operation of hip fracture; each time point is represented as the mean serum level with standard error

Fig. 2  Changes of CTX before and after surgery in elderly hip fracture patients. a Trend of CTX after hip fracture operation in different genders;
b trend of CTX after different operation of hip fracture; each time point is represented as the mean serum level with standard error

OC Different from P1NP and CTX, OC did not show obvious

The mean baseline serum OC level was 13.3 ng/ml and
ranged from 2.2 ng/ml to 33.7 ng/ml. Serum OC levels
increased in 147% (25–75%: 100–201%; p < 0.001) from
baseline to 30–60 days after surgery, and then increased
in 175% (25–75%: 140–216%; p < 0.001) from baseline at
80–120 days and increased in 167% (25–75%: 122–206%;
p < 0.001) from baseline at 180–230 days postoperatives.
decrease at 80–120 days and 180–230 days after operation.
Like CTX, female had higher serum OC level than
male in hip fracture patients over 65 years old (p = 0.054).
And like CTX, there was no difference in OC between
hip replacement group and intramedullary nailing group
(p = 0.658) (Table 2, Fig. 3). There was also no association
between 25(OH)D deficiency (< 20 ng/ml) and serum OC
levels (p = 0.496). However, oldest old patients (≥ 85 years

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242 Journal of Bone and Mineral Metabolism (2021) 39:237–244

Fig. 3  Changes of OC before and after surgery in elderly hip fracture patients. a Trend of OC after hip fracture operation in different genders; b
trend of OC after different operation of hip fracture; each time point is represented as the mean serum level with standard error

Fig. 4  a Changes of CTX before and after surgery in elderly hip fracture patients in different serum 25(OH)D levels; b changes of OC before
and after surgery in elderly hip fracture patients in different ages. Each time point is represented as the mean serum level with standard error

old) was associated with an decrease in serum OC levels
(p < 0.001) (Fig. 4b).
Discussion
Early operation is a clinical treatment to hip fracture to
improve the quality of life and reduce mortality as soon as
possible. The healing of postoperative fracture is a dynamic
process; osteoclasts remove the residual dead bone and
osteoblasts form new bone. Osteoclasts and osteoblasts are
closely related to form bone reconstruction or bone trans-
formation. In this paper, we observed the changes of BTMs
during the process of hip fracture healing. From the general
data, it can be seen that the majority of hip fractures are
female. The hemoglobin, urea nitrogen, and creatinine lev-
els of female patients are lower than that of male patients,
and the BMD value of female hip is lower than that of male

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Journal of Bone and Mineral Metabolism (2021) 39:237–244
patients. It is consistent with the general recognition that the
hemoglobin and muscle contents of male patients are higher
than that of female patients, and the bone density of male
patients is higher than that of female patients of the same
age [18]. And, the level of vitamin D in the elderly patients
with hip fracture is generally insufficient.
When observing the change trend of BTMs, if the
change of P1NP was taken as the standard, which peaked
at 30–60 days post-operative, increased nearly three times
of the baseline level, and did not decline to the baseline
level at the end of our observation; the increase of CTX
was the lowest among the three markers, and it dropped to
the baseline level at 80–120 days, which is the expected
time when the majority of fracture healing is expected;
the special point of OC is that it reached the peak at the
latest, and the decline was slow, at the end of our obser-
vation, only a slight decline occurred. From the above
BTMs’ changes, we can see that the bone resorption rate
has dropped to the baseline level at 80–120 days, while
the bone formation and mineralization of new bone is still
continuing. The changes of the above bone markers are
consistent with the process of fracture healing, especially
after the operation makes the fracture return to a better
alignment, it is expected that the total amount of callus
will be relatively small, and the number of dead bones that
need to be removed by osteoclasts will be less. Therefore,
the bone markers of osteoclast recovered to the baseline
level earlier, while the bone formation and mineralization
lasted longer.
The previous reports on BTMs changes after fracture
have different results, except those reasons mentioned
before in this article, another important point is that the
baseline value of the BTM is different, some of the studies
took blood samples around 2 weeks after the fracture [12],
while at that time, the BTMs were not actually the baseline
[15]; so the changing trends of BTMs and relationship
with other factors will change correspondingly.
The three BTMs observed in this paper were also show
different characteristics in other aspects of the patients.
There was no significant difference in P1NP between male
and female. The trend of curve change of serum CTX
and OC was the same between male and female, while
the curve of female is higher than that of male, which is
related to the osteogenic effect of male androgen and the
protective effect of estrogen on bone metabolism of female
patients [9, 19, 20].
Considering the relationship with different operation,
serum P1NP level in the hip replacement for femoral neck
fractures group was lower than those in the Intramedullary
nailing for intertrochanteric fractures group, and serum
CTX and OC have these trends but without statistic signifi-
cance. The reason lies in the different fracture and opera-
tion methods, intramedullary nail fixation of the femoral
243
intertrochanteric fracture at 30–60 days after surgery was
in the stage of callus formation, osteoclasts continued
to remove the residual dead bone, and intramembranous
osteogenesis and cartilaginous ossification are in progress;
however, at that time with patients with hip replacement
of femoral neck fracture, there is not a lot of residual dead
bone that needs osteoclast removal, nor the formation of
a large amount of callus, so the overall level is not high
[9]. If the study case increases, it is possible to estab-
lish statistical differences on CTX and OC with different
operation type.
Low vitamin D levels have been reported to be associ-
ated with impaired fracture healing [21]. Stewart [12] et al.
reported that baseline serum 25(OH)D < 20 ng/ml would
increase BTMs after fracture, especially for CTX. Our data
showed no association between average serum 25(OH)D
level and BTMs. The relationship of 25(OH)D and BTMs
has been controversial, and any conclusion should be inter-
preted with caution. We should notice the source of the
research population, whether they are healthy, whether they
have osteoporosis, whether their vitamin D is sufficient or
deficiency, and how about the proportion and degree of the
lack; and does the level of vitamin D changed when the end
event occurs; et al. In general, it is good for bone health to
prescribe vitamin D to the patients who are vitamin D insuf-
ficiency or deficiency. And, maybe, the sample size is impor-
tant too; a larger study is easier to found an association [12].
Our study is a rare and detailed prospective study on the
changes of bone turnover markers in patients with differ-
ent hip fracture operation methods, gender, average vitamin
D level during the healing process, and age; our study is
helpful to explore the regular patterns of bone turnover in
the process of hip fracture healing, and find patients with
abnormal rules, so as to make use of diagnosis and treat-
ment. There are also some deficiencies in this paper. First,
the number of cases is not large; second, the observation
time is not very long. It is expected that the follow-up study
can be continued and carried out in the future.
Acknowledgements Not applicable.
Funding Fund project supported this work: Beijing Municipal Admin-
istration of Hospitals Incubating Program, Code: PX 2019015; Beijing
Municipal Health Committee Scientific Research Project, Code: Bei-
jing 19-17.
Compliance with ethical standards
Conflict of interest No competing interests to declare.
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