Spine Deformity (2021) 9:645–653

https://doi.org/10.1007/s43390-020-00262-7

BASIC SCIENCE

Correlation of collagen X biomarker (CXM) with peak height velocity

and radiographic measures of growth in idiopathic scoliosis
Michelle Cameron Welborn1   · Ryan Coghlan1 · Susan Sienko1 · William Horton1

Received: 21 January 2020 / Accepted: 21 November 2020 / Published online: 5 January 2021
© Scoliosis Research Society 2021

Abstract
Study design  Prospective comparative study.
Objectives  Evaluate the correlation of CXM with established measures of growth. Theoretically higher CXM levels would
correlate with rapid longitudinal bone growth and lower levels with growth cessation.
Summary  Assessment of growth status in patients with pediatric spinal deformity is critical. The current gold standards
for assessing skeletal maturity are based on radiographic measures and have large standard errors (SE). Type X collagen
(COLX) is produced in the growing physis during enchondral ossification. CXM is a COLX breakdown product that can be
measured in blood products. CXM, thus, is a direct measure of enchondral ossification.
Methods  IRB-approved prospective study. Q6mo anthropometrics and spine PA biplanar slot scanner images including
the hand were assessed for major Cobb, Risser score (RS), triradiate cartilage status (TRC), Greulich and Pyle bone age
(BA), and Sanders Score (SS). Serial dried blood spots (DBS) to obtain CXM levels were collected 3 consecutive days
Q1–2 months based on SS.
Results  47 idiopathic scoliosis patients, Cobb ≥ 20 were enrolled. Mean enrollment age was 11.8 years (range 7.1–16.6 years).
3103 DBS samples were assayed in quadruplicate. CXM results were highly reproducible with a 3% intraassay coefficient of
variation (CV), and 12% interassay CV%. The CXM 3-day average was significantly correlated with BA R = 0.9, p < 0.001,
RS R = 0.6, p < 0.001, SS R = 0.7, p < 0.001 and with height R = 0.7, p < 0.001. No patient with a CXM level < 5 ng/ml had
remaining growth.
Conclusion  CXM is the first identifiable biomarker specific to longitudinal bone growth. Early results indicate that it is a
patient-specific, real-time measure of growth velocity with high correlation to the established anthropometric and radio-
graphic measures of growth. It is predictive of cessation of growth. It is highly reproducible with a low SE. Long-term
follow-up is required to determine the ability of CXM to guide clinical decision-making.

Keywords  Growth · Scoliosis · Sskeletal maturity · Growth potential · Collagen X · Biomarker

Introduction of physical measurements to be reliably assessed and by then

Assessment of growth and specifically growth veloc-
ity is critically important in nearly all areas of pediatrics.
Growth velocity is used as a surrogate for health status and
improvements in growth velocity are indicative of a positive
response to a nutritional change in malnourished patients or
a treatment regimen in chronically ill patients. Measuring a
change in growth velocity typically requires a year or more
* Michelle Cameron Welborn
mwelborn@shrinenet.org
1
Shriners Hospitals for Children, 3101 SW Sam Jackson Park
Road, Portland, OR 97229, USA
the window for treatment may have already passed [1–3].
This prolonged timeframe greatly impacts pediatric ortho-
pedic surgeons who make decisions based on how much
longitudinal bone growth a patient has remaining. Assess-
ments of growth velocity are particularly important in the
treatment of patients with scoliosis as curve progression is
closely related to both the magnitude of the curvature and
the skeletal maturity of the patient; with curves progressing
faster in times of significant growth [4–8]. Therefore, accu-
rate assessment of a patient’s growth status can mean the
difference between observation, bracing, or surgery. Current
techniques for assessing growth velocity are inadequate in
that they have large standard errors and may take months

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646
or years to reliably assess a patient. At this time, there is
no clinically validated method to assess growth velocity in
real time.
One of the most clinically relevant measures of growth
velocity is peak height velocity (PHV). PHV reflects the
most rapid phase of growth during the adolescent growth
spurt. Peak pubertal growth typically occurs over 2 years;
approximately 1 year before and after PHV. True PHV can
only be ascertained retrospectively by serial height meas-
urements, reducing the feasibility of this measure to guide
the timing of treatment interventions [9, 10]. Radiographic
measures of skeletal maturity have increasingly been used
to gauge the amount of growth that the child has experi-
enced and to extrapolate the amount of growth that remains
[11]. Scoring systems based on radiographs of the pelvis or
hands are the most common methods used to assess PHV.
Previous studies have demonstrated that triradiate cartilage
closure is visible shortly after PHV. Assessment of PHV was
further refined by the Sanders Stage (SS) in which use of
hand radiographs demonstrated that distal digital phalangeal
epiphyses are uncapped pre-PHV and fused post-PHV [5].
Combining scores of multiple radiographic measurements
improves precision and accuracy in the assessment of skel-
etal maturity, but can lag behind the patient’s clinical growth
by 6 months or more [12–15]. Furthermore, radiographic
measures are based on population data of Caucasian female
patients and thus are less accurate for male patients, patients
of noncaucasian racial backgrounds, or patients with growth
abnormalities [16–19].
Due to the variability of radiographic measures, molecu-
lar biomarkers of skeletal maturity have been investigated.
Protein biomarkers such as bone-specific alkaline phos-
phatase (BSAP), N-terminal propeptide of type 1 collagen
(P1NP), urine C-telopeptide of collagen cross-links (CTX-1)
have been studied to assess bone formation and resorption
with varying levels of success [10, 20]. These biomarkers
exhibit varying levels of correlation with height velocity
(HV) measurements; however, they are not specific to lin-
ear bone growth. Sanders et al., performed a comprehensive
study looking at serological, anthropomorphic and radio-
graphic measures of height velocity [5]. Only estradiol and
IGF-1 were found to be discriminatory and only if used in
combination with Tanner stages and the appearance of the
Table 1  Correlation of height
velocity between visits and
radiographic measures of
skeletal maturity
CXM (mean value between visits used
to determine height velocity)
Greulich and Pyle
Risser sign
Sanders stage
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Spine Deformity (2021) 9:645–653
Fig. 1  Depiction of skeletal growth plate: COLX is an extracellular
matrix protein normally produced by growth plate hypertrophic chon-
drocytes. During bone growth, the NC1 portion of COLX (CXM)
is cleaved from the full length protein by proteolytic enzymes and
released into the blood stream via invading blood vessels from the
newly formed bone
epiphyses on radiographs. Osteocalcin, which is specific to
bone formation, was not found to be specific in this study.
This is likely because it is a marker of bone formation as
opposed to elongation (longitudinal bone growth) and thus
it is expressed in both endochondral ossification and apposi-
tional growth [21, 22]. Recently, type X collagen (COLX), a
collagen protein synthesized nearly exclusively in the hyper-
trophic zone of the growth plate of growing long bones has
been identified as a potential marker of growth (Fig. 1); [23].
Coghlan et al. described the discovery of a stable breakdown
product of collagen X (CXM) that can be accurately detected
and quantified from human blood using a proprietary ELISA
immunoassay in which CXM concentration displays a strong
correlation to measured height growth velocity [24]. CXM
exists as a homo-trimeric globular protein that is highly
resistant to freeze/thaw cycling and temperature fluctuations,
allowing the biomarker to be collected and assayed using a
variety of blood components such as plasma, serum, and
dried blood spots (DBS).
We hypothesize that CXM is a direct measure of longitu-
dinal bone growth and, therefore, a non-radiographic method
to detect instantaneous height velocity in growing children.
In this study, we sought to establish the efficacy of CXM as
a measure of growth velocity, compared to the gold standard
All patients Excluding patients < 8 years
Correlation p value Correlation p value
0.7 p < 0.001 0.7 p < 0.001
− 0.9 p < 0.001 − 0.6 p < 0.001
− 0.6 p < 0.001 − 0.7 p < 0.001
− 0.7 p < 0.001 − 0.7 p < 0.001
Spine Deformity (2021) 9:645–653 647
Table 2  Mean CXM values SS Gender Number of Mean
in ng/ml by Sanders stage and Subjects CXM
gender, Sanders scores only level
collected at clinic visits
1 F 8 24.6
2 F 17 28.9
3 F 16 19.4
4 F 8 15.4
5 F 8 12.8
6 F 10 9.6
7 F 17 8.8
As subjects were followed over time, subjects may be included in more than one Sanders score if their skel-
etal maturity changed at subsequent visits
radiographic and anthropometric assessments, in patients
with idiopathic scoliosis.
Methods
This was an IRB-approved prospective cohort, diagnostic
study evaluating growth in skeletally immature children and
adolescents of both genders with idiopathic scoliosis. Inclu-
sion criteria included: age 7 years or older, premenarchal or
less than 1.5 years post menarche for females and a Cobb
angle ≥ 20 degrees at the onset of treatment. Patients with
prior spine fusions, abnormalities of maturation or height,
skeletal dysplasia or dwarfism, as well as pregnant females
were excluded.
At each visit, the following anthropometrics were
measured by trained clinical research personnel: stand-
ing height, (using a wall-mounted stadiometer), arm span,
ulnar length, and weight. Ulnar length was converted to
height using the predictive equations for height based on
ulna length (U) and age in years (A) according to Guald
et al. [25]. For males, height (cm) = 4.605U + 1.308A + 2
8.003; for females, height (cm) = 4.459U + 1.315A + 31.4
85. PA spine films were taken, major Cobb, T1-S1 length,
Risser score (RS), Sanders Stage (SS), and Greulich and
Pyle bone age (GP) were then scored and recorded by the
attending physician. Sauvegrain score was used in the
pilot study, but as it reflected a more limited age range
(11–13 for girls and 13–15 for boys) than our study popu-
lation it was not used in the larger study.
From the previous work of Coghlan et al., it has been
established that the CXM ELISA is able to detect CXM
with great accuracy and limited variation from serum,
plasma, and dried blood spots (DBS) [24]. DBS sam-
pling allows blood specimens to be generated in the con-
venience of the patient’s home without needing special
equipment or advanced training for valid DBS sample
preparation. An initial DBS training session was provided
and a DBS was obtained in clinic to ensure an adequate
Range SS Gender Number of Mean Range
subjects CXM
level
15.4–41.3 1 M 5 18.4 13.4–25.2
14.7–46.5 2 M
11.2–35.7 3 M 6 20.8 13.1–31.4
7.8–22.8 4 M
8.9–19.7 5 M
6.3–12.6 6 M 2 10.3 9.2–11.4
3.7–15.8 7 M 2 16.0 15.7–16.3
understanding of the DBS process and to provide a base-
line sample for measuring CXM concentration. Partici-
pants in SS 1–2 and 7–8 collected DBS samples every
other month while patients with a SS of 3–6, collected
DBS every month. Previous studies have shown that the
CXM biomarker exhibits some diurnal variation, with
less variation in the morning [24]; therefore, participants
were instructed to obtain DBS from three mornings in
the same week within 1  h of waking. All participants
recorded the date, wake time and DBS preparation time
on the DBS card for each spot and then placed completed
DBS cards in a sealed bag with desiccant packs to mail
back to the hospital for storage at -20C. Each DBS speci-
men was punched in duplicate if possible by a 3.1 mm
foot powered DBS puncher supplied by Analytical Sales
and Products Inc. Each punched spot was eluted in 300ul
of sample diluent overnight at 4C and assayed in dupli-
cate the following day according to the ELISA procedure
outlined in Coghlan et al.[24].
Correlation coefficients were used to examine the
relationship between the CXM level and radiographic
measures of skeletal maturity and height velocity (cm/
year). Means and standard deviations were used to exam-
ine CXM levels associated with each SS by gender. Sig-
nificance was set at p ≤ 0.002 to account for multiple
comparisons.
Results
Forty-seven children and adolescents with idiopathic sco-
liosis (39 female, 8 male), mean age 11.8  years (range
7.1–16.6 years) enrolled in the study with a mean coronal
Cobb angle at enrollment of 30 degrees. Each subject com-
pleted a mean of 6.7 months of DBS card collection (range
1–19 months) with each card containing three DBS speci-
mens. Each specimen was assayed in quadruplicate both in
the same plate and in a separate plate to provide an intra and
an inter-assay control. This provided a total of 3103 data
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648
Fig. 2  a CXM concentration data vs. age shown for each individual
in this study, each color representing a different individual. Boys are
in shades of blue. Mean CXM values and SE bars are shown for each
month, with monthly readings connect by a solid line. b CXM con-
centration data vs. measured height growth velocity of individuals in
this study. A non-linear line of best fit is shown in red to fit the data
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Spine Deformity (2021) 9:645–653
(CXM relationship to Height velocity Pearsons r = 0.7). Male and
female data are combined for analysis. c CXM concentration data vs.
SS for individuals in this study. A third order polynomial non-linear
line of best fit is added to the data set in red (CXM relationship to
Sanders score Pearsons r = 0.7). Male and female data is combined
for analysis
Spine Deformity (2021) 9:645–653 649

Fig. 3  Individual CXM readings for each month of a fast growing patient (a) and a slow growing patient (b)

Fig. 4  Gaussian distribution 55 CXM Concentration vs. Age

non-linear fit lines are superim-
posed over CXM vs. Age data 50
where best-fit lines could be cal-
culated. Growth velocity y axis 15
45
added to the right side of the
graph in accordance with the
40
measurements shown in Fig. 2b

Growth
35
fe
1m
100ales

hV
CXM (ng/ml)

males

Velocity
30

e
25

(cm/year)
20
5

15

10

5
0

0
7

10

11

12

13

14

15

16

17

Age (years)

points from 802 DBS samples collected with mean follow-
up between CXM measurements was 8.7 months (range
0.2–18.2 months), with monthly CXM averages used for
analysis.
HV was statistically significantly correlated with all
four skeletal maturity measures (Table 1). Correlations for
both the RS and SS were lower than expected [5], so we
examined whether removing the patients under the age of
8 improved the correlation for these measures. As RS and
SS measures were designed for peripubescent patients and
Sanders described SS1 patients having an average bone age
of 8 years + 10 months and thus the inclusion of patients
below 8 y/o may have influenced the correlation however,
neither correlation improved after removing these subjects.
Overall, the highest average CXM levels were in the
SS2 female patients, and SS3 males (Table 2; Fig. 2c). This
result may be skewed because we did not have any male
SS2 patients, nor did we separate out SS3 into 3a and 3b.
An increased sample size for each SS and males is needed
to accurately determine the CXM level associated with each

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Table 3  Adolescents in SS 7, height velocity, CXM closest to visit Discussion

and the mean CXM between visits
Subject Gender Height Closest CXM Mean CXM (ng/ While physicians have attempted to assess skeletal matu-
velocity (ng/ml) to visit ml) between visits rity and growth velocity in children since the 1940s, they
(cm/yr)
have been doing so with indirect measures generated from
1003 F 1.6 9.6 9.5 outdated population-based data. Currently, the majority of
.6 6.7 7.2 people use RS or bone age to assess growth velocity; how-
.5 5.9 6.5 ever, these are the least accurate techniques particularly in
1014 F 4.0 6.9 6.7 boys, Asians, African Americans, and patients with altered
0.0 4.4 5.7 growth [26].
1015 M 4.9 15.7 18.7 Our preliminary results suggest that CXM is an instanta-
1021 F 3.2 3.3 6.8 neous measure of growth velocity in children. CXM values
1022 F 2.1 9.2 10.1 show a similar trend to SS when compared to HV as shown
1024 M 7.0 16.3 24.6 in Fig. 2c with CXM levels peaking at SS 2 in girls and SS
1027 F 3.4 9.4 11.0 3 in boys and slowly decreasing by SS 7. CXM concentra-
.6 6.5 7.6 tions correlate as well with growth velocity calculations as
1036 F 2.0 6.1 9.1 the current gold standard of radiologic measurements, the
1039 F 2.0 11.0 10.5 SS. But longer term follow-up is needed to fully evaluate
the relationship of CXM and HV to individual SS and RS.
Determining cessation of growth remains challeng-
SS. As HV decreased there was as a concomitant decrease in ing with traditional radiographic measures of growth and
biomarker level while all patients with measurable growth yet is critically important in the nonoperative treatment of
had CXM > 5 ng/ml. scoliosis patients. Hubbard et al. reported on RS 4 patients
Plotting the individual CXM concentration means for the with curves < 50 degrees and found that 25% of patients had
subjects in this study (Fig. 2a) shows the wide range of CXM progression greater than 5 degrees in the 24 months after
values for individuals in this study, only those patients with cessation of bracing [27]. As they used RS for their deter-
a minimum of 6 months of data were included in this figure mination of growth cessation the question arises were those
to show their rate of growth over time. Each data point rep- patients still growing and was that growth responsible for
resents the monthly average for each patient, with range of the curve progression. When compared to SS, utilization
the three specimens collected every month represented by of the RS has been found to result in the mistreatment of 1
the error bars. CXM correlated well with both HV and SS as in 4 patients with AIS treated with bracing and many more
is shown in Fig. 2b, c, with increasing CXM concentrations may be undertreated [14]. But while SS is accurate for deter-
correlating with increasing rate of growth cm/yr. mining the onset of peak growth, the ability to determine
Month to month CXM levels varied more for faster grow- cessation of growth continues to be inadequate and there-
ing children than slower growing children (Fig. 3a, b), but fore the utility in guiding the termination of bracing is lim-
day to day variation when converted to percentages of total ited [28, 29]. Grothaus et al. specifically used SS7 as their
CXM levels was similar for both fast and slow growers. The critieria for brace cessation and found that 20% of patients
average for each 3-day period was generally stable month to experienced > 5 degrees of curve progression [30]. In our
month for most individuals in this study, with less day-to- previous study, we found that CXM vs HV intercepted the
day variance for those individuals nearing the end of their y-axis at ~ 6 ng/ml concentration but rounded to 5 ng/ml for
pubertal growth spurt. When growth velocity is added as an our analysis [24]. In this study, we noted that all our SS7
alternative y-axis as seen in Fig. 4, CXM values can be inter- patients initially had measureable growth remaining and
preted with instantaneous growth velocity measurements. thus SS7 alone does not appear to correlate with growth
These data suggest that measurement of CXM through DBS cessation. This growth occurred when their average CXM
provides an instantaneous measure of growth without the levels between visits was greater than 5 ng/ml. Some SS7
need to wait months or years, thus enhancing our ability to patients did not have measurable growth over the 6 month
determine growth potential and skeletal maturity better than period and in all these patients their ave CXM between vis-
our current radiographic and anthropometric techniques. its was < 5 ng/ml. We did not have any SS8 patients in the
current study, so we are unable to say if the cessation of
clinically significant measurable growth occurs at a later
SS7 stage or SS8. We can say that SS7 alone is insufficient

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Table 4  Patient demographics including number of specimen cards (each card includes 3 samples), change in height and change in sanders score
Gender Age at onset of Age at last visit Number of Ht at beginning Ht at last visit SS at beginning SS at last visit
study (months) DBS cards of the study of the study

F 128.1 146.3 19 153.2 162 2 3

F 159.1 176.6 19 162.6 165.3 4 7
F 171.3 – 1 152.0 – – –
F 168.9 – 2 155.9 – 5 –
F 160.1 175.3 8 151 156 4 7
M 174.1 – 2 178.4 – 3 –
F 168.7 – 2 159 – 6 –
F 169.0 – 1 163.7 – 7 –
F 88.3 98.2 4 128 136.5 1 1
M 174.1 – 2 178.4 – 6 –
F 126.7 141.8 11 144.3 149.3 2 3
F 142.7 158.1 14 146 154.5 3 4
F 154.3 171.0 18 166.2 168.6 6 7
M 169.2 185.4 9 190.3 196.4 3 7
F 147.8 – 3 160.5 – 3 –
F 102.1 118.5 15 137.8 145.7 2 2
F 101.1 – 1 149 – 1 –
F 147.7 149.0 3 160.2 – 5 –
F 157.6 159.3 3 161.8 – 5 –
F 163.1 178.0 12 164.6 166.2 7 7
F 149.8 164.5 15 150.4 154.4 3 7
M 148.7 152.8 6 161.3 – 3 –
M 161.7 175.7 11 161.6 170.4 3 7
F 95.5 109.7 10 133.6 140.5 1 2
M 120.3 122.4 4 141.3 – 1 –
F 141.1 152.6 12 155.3 157.3 3 7
F 163.8 174.2 12 163.2 163.9 4 6
F 150.5 151.6 3 153.9 162.2 2 3
F 124.6 136.8 15 140.5 149.0 2 2
F 160.0 166.7 7 158.2 161.3 3 5
F 97.2 – 1 122.7 – 1 –
F 159.5 169.9 10 163.9 – 4 7
M 84.4 94.9 7 127.4 129 1 1
F 105.6 111.4 4 130.5 132.2 1 –
F 188.4 198.7 9 167 168.5 6 7
F 141.3 – 1 148.1 – 3 –
F 136.9 146.0 9 148.8 153.4 2 2
F 140.4 149.6 11 160.5 161.5 6 7
F 140.3 142.6 3 149.3 151.8 3 6
F 157.9 – 1 155.3 – 3 –
F 140.3 142.6 3 148.5 – 2 –
F 132.6 134.8 3 147 – 2 –
F 162.9 167.0 6 164.4 – 7 –
F 135.8 – 1 157.2 – 3 –
F 88.2 – 1 129 – 1 –
M 172.9 – 1 184.4 – 3 –
F 55.6 – 1 137 – 1 –

– denotes data that was unavailable for that visit

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652
to predict growth cessation indicating that SS7 alone may
not be sufficient for brace cessation as shown in Table 3.
Children in this study tolerated the DBS collection proce-
dure well with a small dropout percentage. Using DBS as a
blood analysis tool allows patients to prepare blood samples
from the convenience of their own home, decreasing the
need for excessive doctor visits and decreasing the total cost
of treating scoliosis patients in the future. Collecting three
daily DBS per month would likely not be feasible for wide
scale adoption of this assay for growth velocity determina-
tions; however our study will continue to collect DBS sam-
ples at this pace for the next four years to gather validation
data to determine the minimum samples required to make
clinical assessments of each patient. In the future, single
DBS samples or a small series of monthly or bi-monthly
preparations may be all that is required to assess the growth
status of scoliosis patients Table 4.
There are limitations to our study, including the relatively
small sample size, which resulted in a lack of patients in
each radiographic scoring category as well as the short dura-
tion of follow-up of some of the patients. The next stage of
the study will be expanded to four centers following these
patients over four years, during which time we will con-
tinue to assess the correlation of CXM with the radiographic
scoring systems and anthropometric measures of growth.
We will also be monitoring the major Cobb angle in our
patients to determine the accuracy of these scoring systems
vs. CXM to predict growth rates associated with Cobb angle
progression.
Future directions include the potential for the biomarker
to assist with, if not replace traditional radiographic meas-
urements for growth velocity determinations in pediatric
medicine in the future. Measuring CXM levels of children
has the potential to give physicians the ability to assess
growth velocity immediately instead of needing to wait
many months or years. This measurement may be particu-
larly useful in scoliosis patients, where decisions such as
when to perform a growth friendly construct vs fusion vs
bracing are dependent on remaining growth.
CXM represents the first marker that is specific to endo-
chondral ossification. Our work has shown that the assay
is highly consistent and reproducible and most importantly
CXM levels are highly correlated with the radiographic
measures of growth. In conclusion, our preliminary results
indicate that CXM biomarker assay is sensitive and specific
to endochondral ossification and physeal activity. It is sta-
tistically correlated to all known measures of skeletal matu-
rity. Thus, our preliminary data have shown that CXM has
the potential to be a patient specific, low risk, radiation-free
measure of skeletal maturity.
“All procedures performed in studies involving human
participants were in accordance with the ethical standards of
the institutional and/or national research committee (include
13
Spine Deformity (2021) 9:645–653
name of committee + reference number) and with the 1964
Helsinki declaration and its later amendments or comparable
ethical standards.”
Author contribution  MCW: Conception/design, data acquisition,
analysis, interpretation, drafted/revised work, and approved final ver-
sion. RC: Conception/design, data acquisition, analysis, interpretation,
drafted/revised work, and approved final version. SS: Conception/
design, data acquisition, analysis, interpretation, drafted/revised work,
and approved final version. WH: Conception/design, interpretation,
drafted/revised work, and approved final version. All authors agree to
be accountable for all aspects of the work in ensuring that questions
related to the accuracy or integrity of any part of the work are appro-
priately investigated and resolved.
Funding  POSNA Research Startup Grant; Shriners Hospital for Chil-
dren Directed Research Grant.
Compliance with ethical standards 
Conflict of interest  Dr. Welborn reports grants from POSNA, grants
from Shriners Hospital for Children, during the conduct of the study;
personal fees and other from Depuy Synthes, personal fees from Nu-
vasive, personal fees from Stryker/K2M, outside the submitted work.
Mr. Coghlan reports grants from POSNA, grants from Shriners Hos-
pital for Children, during the conduct of the study; personal fees from
BioMarin, personal fees from Therachon, personal fees from QED
therapeutics outside the submitted work. Dr. Sienko reports grants
from POSNA, grants from Shriners Hospital for Children, during the
conduct of the study. Dr. Horton reports grants from POSNA, grants
from Shriners Hospital for Children, during the conduct of the study;
personal fees from Biomarin, personal fees from Ascendis Pharma,
personal fees from Theracon, personal fees from QED Therapeutics,
personal fees from Relay Therapeutics, outside the submitted work.
Ethical approval  This is a Western IRB approved study.
Informed consent  Informed consent was obtained from all patients
and their parents.
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