Original Article
Gynecol Obstet Invest 2012;74:143–150
DOI: 10.1159/000339934
Changes in Serum Levels of Cartilage
Oligomeric Matrix Protein after
Estrogen and Alendronate Therapy in
Postmenopausal Women
Seok Kyo Seo a, c Hyo In Yang a, c Kyung Jin Lim a, c Young Eun Jeon b, c
Young Sik Choi a, c SiHyun Cho b, c Byung Seok Lee b, c
a
Department of Obstetrics and Gynecology, Severance Hospital, and b Department of Obstetrics and Gynecology,
Gangnam Severance Hospital, Yonsei University College of Medicine, and c Institute of Women’s Life Medical
Science, Seoul, Korea
Key Words
Cartilage oligomeric matrix protein ⴢ Osteoarthritis ⴢ
Estrogen ⴢ Alendronate ⴢ Menopause
Abstract
Background: Cartilage oligomeric matrix protein (COMP) is
a biomarker for joint destruction and its serum levels are
used for assessing therapeutic efficacy. This study aims to
compare changes in serum COMP levels in postmenopausal
women with osteopenia/osteoporosis receiving estrogen
and alendronate. Methods: A total of 62 postmenopausal
women diagnosed with osteopenia or osteoporosis were
treated with either estrogen (17␤-estradiol 1 mg, n = 30) or
bisphosphonate (alendronate 5 mg, n = 32) for 6 months. The
controls were healthy postmenopausal women (n = 30). Se-
rum COMP and osteocalcin levels were measured at baseline
and after 6 months of treatment. Results: Estrogen de-
creased levels of COMP at 6 months compared to baseline
levels (–8.35 8 19.38%), whereas the bisphosphonate and
control groups resulted in no significant changes (–5.50 8
18.69 and –1.49 8 25.34%, respectively). Concentrations of
osteocalcin decreased significantly in both treatment groups
© 2012 S. Karger AG, Basel
0378–7346/12/0742–0143$38.00/0
Fax +41 61 306 12 34
E-Mail karger@karger.ch Accessible online at:
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Received: August 4, 2011
Accepted after revision: June 3, 2012
Published online: September 4, 2012
(estrogen –25.60 8 24.42% and alendronate –13.76 8
23.89%, respectively). There was a significant positive corre-
lation between changes after 6 months in COMP and osteo-
calcin (R = 0.48, p = 0.002). Conclusions: Postmenopausal
women treated with estrogen showed significantly de-
creased levels of COMP after 6 months. Estrogen might pro-
vide a further treatment modality in the prevention of joint
destruction. Copyright © 2012 S. Karger AG, Basel
Introduction
Osteoarthritis (OA) is the leading cause of disability
with significant socioeconomic consequences and the
major health problem in postmenopausal women, along
with osteoporosis [1]. The prevalence of OA in Korea has
been rapidly increasing and physician-diagnosed OA oc-
curs in more than 45% of adults older than 70 years and
in more than 18% of adults ages 50–59 years [2]. It is now
generally recognized that OA is a complex multifactorial
disease process involving the whole synovial joint, in-
cluding articular cartilage, subchondral bone, synovium,
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Univ. of Michigan, Taubman Med.Lib.
Byung Seok Lee, MD
Department of Obstetrics and Gynecology
Gangnam Severance Hospital, Yonsei University College of Medicine
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146-92 Dogok-dong, Gangnam-gu, Seoul 135-720 (Korea)
Tel. +82 2 2019 3430, E-Mail dr222 @ yuhs.ac
and tendons. Increased bone remodeling is a frequent
finding in studies of OA joints, thus, subchondral bone
turnover has attracted attention with antiresorptives,
such as estrogen and bisphosphonates, representing po-
tentially disease-modifying therapies [3–6].
The dramatic rise in OA prevalence among postmeno-
pausal women indicates a potential protective role of es-
trogens against the development of OA [7]. Among the
WHI cohort of healthy postmenopausal women, more
than 40% reported having been diagnosed with osteoar-
thritis [1] and several epidemiologic studies provide evi-
dence that estrogen therapy is associated with a reduction
in the risk of knee and hip OA [8, 9]. Furthermore, it has
long been reported the effects of estrogen deficiency on
joint components including both articular cartilage and
periarticular bone in cell cultures, animal models, and
humans [10–16].
Although bisphosphonate is an effective inhibitor of
osteoclastic bone resorption, as shown by the reduction
in bone turnover in studies of postmenopausal osteopo-
rosis, there have been inconsistent findings for its effects
on cartilage in animal and clinical studies. Several groups
of investigators have demonstrated that bisphosphonates
show promise for cartilage preservation to a degree [4, 17,
18]. A recent preclinical study demonstrated that ‘pre-
emptive chronic’ bisphosphonate treatment increased
bone mineral density (BMD) and was chondroprotective
in rat models of joint degeneration. These investigators
suggested that delayed initiation of intervention caused
reduced efficacy, and it should be noted that the efficacy
of bisphosphonates in OA may depend upon the disease
stage at which treatment is initiated [18]. Thus, early in-
tervention with bisphosphonates for postmenopausal os-
teoporosis would also have preventive benefits for OA
since cartilage damage may be increased by osteoporosis
after menopause [19]. To date, there has been limited ev-
idence as to whether bisphosphonates were effective ther-
apy for preserving articular cartilage in postmenopausal
women diagnosed with osteoporosis only.
Cartilage oligomeric matrix protein (COMP), a non-
collagenous extracellular matrix protein expressed in
musculoskeletal tissue, mainly in cartilage, has emerged
as a marker of cartilage turnover and joint destruction
associated with OA [20]. It is synthesized by chondro-
cytes and secreted in the form of fragments first into sy-
novial fluid and subsequently into serum, making it rela-
tively simple to monitor in evaluation of the extent of ar-
ticular damage and/or therapeutic efficacy of treatment
[21]. Arthritis and joint injury studies indicate that serum
levels of COMP can be used as a prognostic indicator for
144 Gynecol Obstet Invest 2012;74:143–150
the future progression of joint destruction as well as a
marker for cartilage turnover. In particular, it was ob-
served that cartilage defects might precede the onset of
clinical and radiographic disease, and COMP predicted
subsequent cartilage loss on MRI and thus appeared a
useful biomarker of early OA [22]. However, among the
many reports on serum COMP concentrations, no study
has been conducted to observe the changes in serum
COMP levels after bone antiresorptive agents targeting
postmenopausal women without clinical OA.
In this study, we examined whether estrogen and
bisphosphonate treatments of 6 months had beneficial ef-
fects on cartilage preservation in postmenopausal wom-
en with decreased BMD using measurements of serum
levels of COMP.
Methods
Subjects
This study included 92 healthy, postmenopausal women aged
48–65 years, who were recruited from outpatient clinics at the
Department of Obstetrics and Gynecology of the Gangnam Sev-
erance Hospital, Yonsei University College of Medicine in Seoul,
Korea between April 2008 and February 2009. All subjects had
been postmenopausal for at least 1 year and visited a hospital to
receive menopausal care. None of the participants had any clini-
cally significant medical history including diseases known to af-
fect bone turnover (hyperparathyroidism, renal insufficiency,
diabetes mellitus, thyroid disorders, malignancy) and took any
medication known to affect bone and cartilage metabolism for 6
months prior to the study. These women also had neither history
nor classical symptoms of OA involving peripheral or axial joints
at the baseline interview.
Approval for the study was given by the Institutional Review
Board of Gangnam Severance Hospital, and informed consent
was obtained from all subjects.
Study Design and Measurements
Study visits were scheduled at baseline and at 6 months after
treatment. Thirty women received 1.0 mg 17␤-estradiol plus 2.0
mg drospirenone, and 32 women were treated with 5 mg alendro-
nate, the dosage used for postmenopausal osteoporosis. Thirty
postmenopausal women were matched for age and BMI with the
study subjects, and enrolled as controls.
At initial evaluation, body height and weight were assessed,
and BMI was calculated as the weight divided by the height
squared (kg/m2). BMD at baseline was measured at the lumbar
spine (L1–4) and total hip by dual-energy X-ray absorptiometry
(Hologic QDR 4500A, Waltham, Mass., USA) in women receiving
treatments. Diagnosis of osteoporosis or osteopenia was based on
the World Health Organization criteria; T-score of bone density
falling more than 2.5 SD below the mean values in healthy young
adults or between 1 and 2.49 SD, respectively.
Morning fasting blood samples were obtained at baseline and
at 6 months after treatment, to measure parameters of cartilage
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 Table 1. Baseline characteristics and biomarkers for postmenopausal women treated with either estradiol or
alendronate and controls

ET ALN Control p
(n = 30) (n = 32) (n = 30)

Age, years 53.8685.64 56.0388.09 56.5084.02 0.225

BMI 21.3084.13 22.2983.19 22.3982.23 0.603
Height, cm 156.2783.09 156.8084.69 158.4683.55 0.511
Weight, kg 55.3982.72 54.6686.84 56.2586.20 0.360
Years since menopause 3.2982.55 5.7684.82 5.6384.55 0.118
COMP, ng/ml 40.41812.44 39.90810.58 43.2089.88 0.495
Osteocalcin, ng/ml 21.1688.09 19.3387.52 20.83810.70 0.685

Values are expressed as mean 8 SD. ALN = Alendronate.

Table 2. Baseline values of BMD (in g/cm2) in the two treatment
groups
ET (n = 30) ALN (n = 32) p
Lumbar spine 0.9280.13 0.7780.16 <0.001
Total hip 0.6780.08 0.6280.13 0.081
Values are expressed as mean 8 SD. ALN = Alendronate.
and bone turnover. Centrifuged samples were kept frozen at
–70 ° C until required for the biomarker assay. COMP was mea-
sured in serum by a competitive enzyme-linked immunosorbent
assay (K-ASSAY쏐, Kamiya Biomedical Company, Seattle, Wash.,
USA), using rabbit polyclonal antibodies directed to human
COMP. The intra-assay coefficient of variations was 8.15%. All
samples from each individual were measured in the same ana-
lytical run to avoid inter-assay variability. Serum osteocalcin was
assessed by means of an automated electrochemiluminescence
immunoassay (Modular Analytics E170, HITACHI, Japan). Intra-
and interassay variances were 6.0 and 4.45%, and the normal
range was 15–46 ng/ml.
Statistical Analysis
Statistical calculations were performed using SAS software,
version 9.1.3 (SAS Institute, Cary, N.C., USA). The normality of
the data distribution among different groups was tested according
to the Kolmogorov-Smirnov test. Significant differences in the
baseline characteristics of the different intervention groups were
compared using one-way analysis of variance (ANOVA), followed
by a post-hoc Dunnett test, or independent t test, as appropriate.
Comparisons between time points were assessed with the use of
repeated-measures ANOVA with intervention as between-subject
factor. Adjustment for multiple comparisons was made by the
Bonferroni method. Correlations were examined using the Pear-
son correlations coefficient test for changes in COMP and osteo-
calcin levels over the intervention. Statistical differences were
considered significant if the p value was less than 0.05.
Results
There were no statistically significant differences
among the baseline clinical characteristics including age,
height, weight, BMI, years since menopause, and baseline
levels of the COMP and osteocalcin among the groups
(table 1).
In women receiving alendronate, BMD was signifi-
cantly lower than those in the estrogen therapy (ET)
group at the lumbar spine (0.77 8 0.16 vs. 0.92 8 0.13 g/
cm2, p ! 0.001), but not at the total hip (table 2).
The group receiving estrogen therapy (ET) presented
a marked decrease in serum levels of COMP compared
to the alendronate and control groups after 6 months
(fig.  1a). Repeated measures ANOVA, taking into ac-
count two measurements in the same individual, showed
that the response in serum COMP in the ET group was
dependent on time (p = 0.007), and this time dependen-
cy did not differ significantly among the three groups
(time ! treatment) (p = 0.593). There was a substantial
decrease in COMP in the ET group (–8.35 8 19.38%) by
the paired t test, but the percent changes of COMP lev-
els did not differ among the three groups (alendronate
group –5.50 8 18.69%; control group –1.49 8 25.34%, p =
0.521; fig. 2a).
There was a time-by-treatment effect for osteocalcin
(p ! 0.001), such that the ET and alendronate groups
demonstrated significant decreases in osteocalcin (p !
0.001, p = 0.003, respectively), and the control group
showed no significant changes (p = 0.999; fig. 1b). These
decrements corresponded to percent changes of –25.60 8
24.42% in the ET group, –13.76 8 23.89% in the alendro-
nate group, and 5.68 8 23.16% in the control group, and
there were significant differences in both intervention
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Estrogen/Alendronate Effects on COMP Gynecol Obstet Invest 2012;74:143–150 145

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 50 ET 30
48 ALN
Control 25

Osteocalcin (ng/ml)
46

COMP (ng/ml)
44 20
42
Fig. 1. Change in serum levels of COMP (a) 40 15 **
and osteocalcin (b) after treatment for 6 38
10
months. Subjects consisted of those who 36 *
received either estradiol 1 mg or alendro- 34 5
nate 5 mg daily, and the control group. 32
30 0
Data are presented as mean 8 SE. Data 0 6 0 6
were assessed with use of repeated-mea- a Time (months) b Time (months)
sure ANOVA with time as the within-sub-
ject factor and intervention as the be- 1
tween-subject factor. *  No significant ef-
fect of treatment for changes in COMP
levels among ET, ALN and control (p = 0 20

Percent change of osteocalcin

0.593). **  Significant effect of treatment
Percent change of COMP

–2 10
for changes in osteocalcin levels among
ET, ALN and control (p ! 0.001). ALN = –4
0
Alendronate. –6
–10
Fig. 2. Average changes in serum COMP –8
(a) and osteocalcin levels (b) after 6 months –20
in the groups treated with estrogen and
–10 *
–12 –30
alendronate, and control. Values are
mean 8 SE. Asterisks (*) denote signifi- –14 –40
*
cance as compared to the control group; a ET ALN Control b ET ALN Control
ET, p = 0.001 and ALN, p = 0.023. ALN =
Alendronate. 2

groups versus the control group (p = 0.001 in ET group,

p = 0.023 in the alendronate group, respectively; fig. 2b).
25
There was a significant positive correlation between
changes after 6 months in COMP and osteocalcin (R =
Osteocalcin change

20
0.48, p = 0.002; fig. 3).
15

R = 0.48
10 p = 0.002
Discussion
5
We investigated whether estrogen and bisphosphonate
0
–5 0 5 10 15 20 25 would have additional benefits of articular cartilage as
–5 COMP change measured by a biomarker of COMP in a group of gener-
ally healthy postmenopausal women. No previous studies
–10 have examined the effects of antiresorptive drug use on
COMP level in postmenopausal women with osteopenia
or osteoporosis. In the present study, estrogen signifi-
Fig. 3. Correlation between the changes in serum levels of COMP cantly reduced the serum levels of COMP in postmeno-
and osteocalcin in postmenopausal women with estrogen and pausal women, supporting the notion that estrogen ther-
alendronate after 6 months. apy might have a chondroprotective effect on OA pro-
gression [16, 23]. Our data were in line with a previous
study indicating that oral and transdermal estradiol had
an effect on cartilage turnover reflected in a decrease of
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146 Gynecol Obstet Invest 2012;74:143–150 Seo /Yang /Lim /Jeon /Choi /Cho /Lee
             
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about 25% in urinary concentration of collagen type II
C-telopeptide degradation products (CTX-II) in healthy
postmenopausal women [23]. Treatment of postmeno-
pausal women with a selective-estrogen receptor modu-
lator (SERM) also caused a decrease in CTX-II, suggest-
ing potential therapeutic benefits of SERM in the preven-
tion of destructive joint diseases [24]. There has been
little work regarding COMP changes after estrogen ther-
apy, and the studies that have been carried out focused on
disorders other than postmenopausal osteoporosis. One
study showed that hormone therapy decreased serum
COMP in postmenopausal patients with rheumatoid ar-
thritis [25].
Although the current study does not identify whether
the observed decrease of COMP levels is attributed to
direct or indirect effects of the estrogen on articular car-
tilage [26], the role of estrogen in the pathogenesis of
common arthritis affecting women around the time of
menopause remains controversial. The effects of estro-
gen on cartilage metabolism and its receptors of chon-
drocytes have been demonstrated in many experimental
and clinical studies of both, degenerative and inflamma-
tory arthritis [13, 24, 27]. Estrogen also has a well-docu-
mented effect on bone turnover, which may play a role in
subchondral bone changes seen in degenerative arthritis
[14].
We did not conduct this study to be aimed at subjects
with clinically or radiologically manifested OA. Howev-
er, these women might be considered as a relevant high-
risk population for developing OA based on their age,
which corresponds to accelerated bone degeneration due
to estrogen deficiency [24, 28]. It is well established that
OA prevalence increases with age- and sex-specific dif-
ferences occurring after the age of 50, when OA or its
predisposition became more prevalent in women [29, 30].
In addition, it should be noted that timely identification
of high-risk patients and monitoring of the quantitative
effect of putative agents for the prevention of OA are of
immense clinical importance for affected individuals.
Currently, diagnosis and monitoring of OA is primarily
based on radiographic findings and patient symptoms.
Available clinical and radiographic methods of OA as-
sessment, however, can provide only insensitive mea-
sures, especially in the early stage [23]. Plain films relate
poorly to patient symptoms, abnormalities occur rela-
tively late in the disease, and MRI, which has been vali-
dated as an accurate and reproducible tool [3], remains
expensive. These observations reflect the fact that current
methodological difficulties in detecting and closely fol-
lowing incipient OA lesions at early stages in postmeno-
Estrogen/Alendronate Effects on COMP
pausal women are major obstacles to better management
for progressive loss of articular cartilage. In this context,
the use of biochemical markers may enable identification
of those patients most likely to progress to OA, and to
more rapidly assess the efficacy of therapies in clinical
trials [22].
Remodeling of cartilage is regulated through activity
of the chondrocytes, which produce both catabolic and
anabolic proteins that maintain the balance between the
breakdown and synthesis of extracellular matrix. COMP
has been shown to interact with chondrocytes, to influ-
ence the organization of collagen fibrils, and to maintain
the extracellular collagen network [28]. As mentioned
above, it has been reported that early OA is often unno-
ticed by the patient and the physician. The literatures sur-
rounding this consideration suggested that serum level of
COMP might be of great value in the early diagnosis of
joint disease [31]. It is increasingly recognized that the
very earliest pathological changes of OA take place peri-
articularly, which are not captured well on plain film but
are evident on MRI. However, elevated serum COMP lev-
els were observed in early-stage OA, including patients
with pre-radiographic OA [32]. Furthermore, COMP has
been considered a potential prognostic indicator of future
joint damage and used to identify persons at higher risk
of OA progression [28, 33, 34]. The Boston Osteoarthritis
Knee Study group assessed a number of markers of car-
tilage turnover and showed that only the baseline level of
COMP was predictive of subsequent MRI-determined
cartilage loss in the OA knee [22]. By contrast, other bio-
chemical markers of cartilage synthesis, turnover, and
degradation including CTX-II might come later as a pro-
gression of OA. We therefore measured COMP concen-
trations at baseline and after treatment as a diagnostic
and monitoring tool for cartilage turnover in postmeno-
pausal women.
There is increasing evidence to support a close bio-
chemical, biomolecular, and mechanical association be-
tween subchondral bone and cartilage in the progression
of OA [4, 18, 35], and subchondral bone displays de-
creased bone mineral content and quality, increased
turnover and resorption [36]. Therefore, one of the most
commonly used antiresorptive agents, bisphosphonate,
may influence periarticular bone changes in OA and
could have an effect on the course of the disease, includ-
ing the possibility of slowing its development and pro-
gression [6]. Alendronate, a nitrogen-containing bisphos-
phonate, has the effect of reducing bone turnover in post-
menopausal osteoporosis by inhibiting the differentiation
and recruitment of osteoclasts and reducing the activity
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Gynecol Obstet Invest 2012;74:143–150 147
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of the resorptive cells at the level of the remodeling unit
[37]. The presented data suggested that bone resorption
could be attenuated without secondary positive effects
on cartilage degradation in those patients who received
5 mg/day of alendronate, which was suggested to be the
clinical dose used for the treatment of osteoporosis. Our
results coincided with previous study in part, which have
shown that alendronate dosage of 20 mg/day rapidly sup-
pressed urinary CTX-II levels to 50% of baseline levels in
postmenopausal women [38]. However, the lower 10-mg
dose, used for the treatment of osteoporosis, had no effect
on CTX-II, and is sufficient to suppress C-terminal telo-
peptide fragments of type I collagen (CTX-I).
There have been clinical trials regarding the effects of
bisphosphonates on cartilage aimed at patients with ex-
isting OA or advanced stage. Treatment with risedronate
reduced the level of CTX-II in patients with knee OA over
two years, although no effect on signs or symptoms or
alterations of the progression of OA was observed [17]. A
longitudinal radiographic study examining the effects of
risedronate at 15 mg/day or 50 mg/week showed that
preservation of the structural integrity of the subchon-
dral bone in knee OA in patients with marked cartilage
loss [39]. These data suggested that the results were at-
tributed to high doses of bisphosphonates as well as their
repeated administration, which might contribute to en-
hanced bone accretion and formation, leading to protec-
tion of articular cartilage.
In contrast, a previous preclinical study showed that
alendronate significantly increased subchondral bone
mass, greatly changed the microarchitecture, increased
bone mineral content and density, and led to accelerated
articular cartilage degeneration in a guinea pig model,
the best-characterized model of primary nontraumatic
OA [40]. Another study demonstrated that alendronate
accelerated sunchondral bone repair in the early stage of
progression in a rabbit model of osteochondral defect, but
that continuous administration inhibited subchondral
bone remodeling [41]. These investigators suggested that
the effects of alendronate differed depending on the time
of administration; Alendronate accelerated new bone for-
mation for the first 8 weeks but impaired remodeling over
the following 16 weeks, thus having both positive and
negative effects on the repair of an osteochondral defect.
A more recent study showed that zoledronate suppressed
both bone and cartilage resorption by inhibition of osteo-
clastic activity in a rat model of degenerative joint disease,
but its efficacy was reduced when treatment was delayed
[18]. These disagreements about the efficacy of bisphos-
phonates on cartilage preservation need to be further val-
148 Gynecol Obstet Invest 2012;74:143–150
idated, and additional clinical studies are needed to elu-
cidate an explanation for these findings.
In accordance with previous studies, we observed that
both estrogen and alendronate caused a significant de-
crease in osteocalcin levels consistent with those agents
being well-known inhibitors of increased bone turnover.
Furthermore, this study showed modest correlations be-
tween changes in COMP and osteocalcin concentrations,
which reflected the fact that their effects on cartilage
were partly related to their effects on bone. Although os-
teocalcin detected from serum samples is considered to
be a marker of bone turnover as well as of bone formation
[42], in vitro studies have demonstrated that osteoblasts
of subchondral bone in OA had abnormal phenotypes,
such as increased release of osteocalcin, suggesting me-
tabolism of osteocalcin might be associated with the de-
velopment of OA [43, 44]. Recent work using ultrasonog-
raphy in women with early-stage knee OA has suggested
that osteocalcin is associated with tendon calcification, a
finding with damage of articular cartilage [35].
This study has several limitations. Although asymp-
tomatic women were included, we had no radiographic
evaluation, and no direct correlation could be performed
between the levels of serum COMP and clinical assess-
ment of OA. Only 6 months of follow-up and the limited
number of subjects hampered our ability to come to a
precise conclusion about the effects of alendronate on ar-
ticular cartilage, and other bisphosphonates or dosages
might be associated with different results. In addition,
since this study was not a randomized study, patients
were assigned based on their decision to take estrogen or
alendronate. Therefore, this might have led to a possibil-
ity that women with menopausal symptoms have chosen
to take estrogen, resulting in younger age in the estrogen
group compared to the alendronate group although not
statistically significant.
In summary, estrogen significantly reduced the serum
levels of COMP in postmenopausal women with low
bone density, indicating that it may protect against the
development of cartilage degradation. Although alendro-
nate was not sufficient to inhibit cartilage matrix degra-
dation, the putative favorable effect of bisphosphonate on
cartilage should be confirmed in future clinical investi-
gations.
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 References
1 Wright NC, Riggs GK, Lisse JR, Chen Z: Self-
reported osteoarthritis, ethnicity, body mass
index, and other associated risk factors in
postmenopausal women-results from the
Women’s Health Initiative. J Am Geriatr Soc
2008;56:1736–1743.
2 Ministry of Health and Welfare: 2005 Na-
tional Health and Nutrition Examination
Survey – Summary. Seoul, Ministry of
Health and Welfare, 2006.
3 Carbone LD, Nevitt MC, Wildy K, et al: The
relationship of antiresorptive drug use to
structural findings and symptoms of knee
osteoarthritis. Arthritis Rheum 2004; 50:
3516–3525.
4 Hayami T, Pickarski M, Wesolowski GA, et
al: The role of subchondral bone remodeling
in osteoarthritis: reduction of cartilage de-
generation and prevention of osteophyte for-
mation by alendronate in the rat anterior
cruciate ligament transection model. Arthri-
tis Rheum 2004;50:1193–1206.
5 Karsdal MA, Leeming DJ, Dam EB, et al:
Should subchondral bone turnover be tar-
geted when treating osteoarthritis? Osteoar-
thritis Cartilage 2008;16:638–646.
6 Kadri A, Funck-Brentano T, Lin H, et al: In-
hibition of bone resorption blunts osteoar-
thritis in mice with high bone remodelling.
Ann Rheum Dis 2010;69:1533–1538.
7 Oliveria SA, Felson DT, Klein RA, Reed JI,
Walker AM: Estrogen replacement therapy
and the development of osteoarthritis. Epi-
demiology 1996;7:415–419.
8 Nevitt MC, Cummings SR, Lane NE, et al:
Association of estrogen replacement therapy
with the risk of osteoarthritis of the hip in
elderly white women. Study of Osteoporotic
Fractures Research Group. Arch Intern Med
1996;156:2073–2080.
9 Spector TD, Nandra D, Hart DJ, Doyle DV:
Is hormone replacement therapy protective
for hand and knee osteoarthritis in women?
The Chingford Study. Ann Rheum Dis 1997;
56:432–434.
10 Hoegh-Andersen P, Tanko LB, Andersen TL,
et al: Ovariectomized rats as a model of post-
menopausal osteoarthritis: validation and
application. Arthritis Res Ther 2004;6:R169–
R180.
11 Oestergaard S, Sondergaard BC, Hoegh-An-
dersen P, et al: Effects of ovariectomy and es-
trogen therapy on type II collagen degrada-
tion and structural integrity of articular car-
tilage in rats: implications of the time of
initiation. Arthritis Rheum 2006; 54: 2441–
2451.
12 Olson EJ, Lindgren BR, Carlson CS: Effects
of long-term estrogen replacement therapy
on the prevalence and area of periarticular
tibial osteophytes in surgically postmeno-
pausal cynomolgus monkeys. Bone 2007;41:
282–289.
Estrogen/Alendronate Effects on COMP
13 Richmond RS, Carlson CS, Register TC,
Shanker G, Loeser RF: Functional estrogen
receptors in adult articular cartilage: estro-
gen replacement therapy increases chondro-
cyte synthesis of proteoglycans and insulin-
like growth factor binding protein 2. Arthri-
tis Rheum 2000;43:2081–2090.
14 Sniekers YH, Weinans H, van Osch GJ, van
Leeuwen JP: Estrogen is important for main-
tenance of cartilage and subchondral bone in
a murine model of knee osteoarthritis. Ar-
thritis Res Ther 2010;12:R182.
15 Sowers MR, McConnell D, Jannausch M,
Buyuktur AG, Hochberg M, Jamadar DA:
Estradiol and its metabolites and their asso-
ciation with knee osteoarthritis. Arthritis
Rheum 2006;54:2481–2487.
16 Zhang Y, McAlindon TE, Hannan MT, et al:
Estrogen replacement therapy and worsen-
ing of radiographic knee osteoarthritis: the
Framingham Study. Arthritis Rheum 1998;
41:1867–1873.
17 Bingham CO 3rd, Buckland-Wright JC,
Garnero P, et al: Risedronate decreases bio-
chemical markers of cartilage degradation
but does not decrease symptoms or slow ra-
diographic progression in patients with me-
dial compartment osteoarthritis of the
knee: results of the two-year multinational
knee osteoarthritis structural arthritis
study. Arthritis Rheum 2006; 54: 3494–
3507.
18 Strassle BW, Mark L, Leventhal L, et al: Inhi-
bition of osteoclasts prevents cartilage loss
and pain in a rat model of degenerative joint
disease. Osteoarthritis Cartilage 2010; 18:
1319–1328.
19 Calvo E, Castaneda S, Largo R, Fernandez-
Valle ME, Rodriguez-Salvanes F, Herrero-
Beaumont G: Osteoporosis increases the se-
verity of cartilage damage in an experimen-
tal model of osteoarthritis in rabbits.
Osteoarthritis Cartilage 2007;15:69–77.
20 Hecht JT, Deere M, Putnam E, et al: Charac-
terization of cartilage oligomeric matrix
protein (COMP) in human normal and pseu-
doachondroplasia musculoskeletal tissues.
Matrix Biol 1998; 17:269–278.
21 Petersson IF, Boegard T, Svensson B, Heine-
gard D, Saxne T: Changes in cartilage and
bone metabolism identified by serum mark-
ers in early osteoarthritis of the knee joint.
Br J Rheumatol 1998;37:46–50.
22 Hunter DJ, Li J, LaValley M, et al: Cartilage
markers and their association with cartilage
loss on magnetic resonance imaging in knee
osteoarthritis: the Boston Osteoarthritis
Knee Study. Arthritis Res Ther 2007;9:R108.
23 Ravn P, Warming L, Christgau S, Christian-
sen C: The effect on cartilage of different
forms of application of postmenopausal es-
trogen therapy: comparison of oral and
transdermal therapy. Bone 2004; 35: 1216–
1221.
Gynecol Obstet Invest 2012;74:143–150
24 Christgau S, Tanko LB, Cloos PA, et al: Sup-
pression of elevated cartilage turnover in
postmenopausal women and in ovariecto-
mized rats by estrogen and a selective estro-
gen-receptor modulator (SERM). Meno-
pause 2004;11:508–518.
25 Forsblad d’Elia H, Christgau S, Mattsson
LA, et al: Hormone replacement therapy,
calcium and vitamin D3 versus calcium
and vitamin D3 alone decreases markers of
cartilage and bone metabolism in rheuma-
toid ar thritis: a randomized controlled trial
(ISRCTN46523456). Arthritis Res Ther
2004;6:R457–R468.
26 Tanko LB, Sondergaard BC, Oestergaard S,
Karsdal MA, Christiansen C: An update re-
view of cellular mechanisms conferring the
indirect and direct effects of estrogen on ar-
ticular cartilage. Climacteric 2008;11:4–16.
27 Richette P, Dumontier MF, Tahiri K, et al:
Oestrogens inhibit interleukin 1beta-medi-
ated nitric oxide synthase expression in ar-
ticular chondrocytes through nuclear fac-
tor-kappa B impairment. Ann Rheum Dis
2007;66:345–350.
28 Sowers MF, Karvonen-Gutierrez CA, Yosef
M, et al: Longitudinal changes of serum
COMP and urinary CTX-II predict X-ray de-
fined knee osteoarthritis severity and stiff-
ness in women. Osteoarthritis Cartilage
2009;17:1609–1614.
29 Hanna FS, Teichtahl AJ, Wluka AE, et al:
Women have increased rates of cartilage loss
and progression of cartilage defects at the
knee than men: a gender study of adults
without clinical knee osteoarthritis. Meno-
pause 2009;16:666–670.
30 Srikanth VK, Fryer JL, Zhai G, Winzenberg
TM, Hosmer D, Jones G: A meta-analysis of
sex differences prevalence, incidence and se-
verity of osteoarthritis. Osteoarthritis Carti-
lage 2005;13:769–781.
31 Neidhart M, Hauser N, Paulsson M, DiCe-
sare PE, Michel BA, Hauselmann HJ: Small
fragments of cartilage oligomeric matrix
protein in synovial fluid and serum as mark-
ers for cartilage degradation. Br J Rheumatol
1997;36:1151–1160.
32 Dragomir AD, Kraus VB, Renner JB, et al:
Serum cartilage oligomeric matrix protein
and clinical signs and symptoms of potential
pre-radiographic hip and knee pathology.
Osteoarthritis Cartilage 2003;10:687–691.
33 Posey KL, Hecht JT: The role of cartilage
oligomeric matrix protein (COMP) in skel-
etal disease. Curr Drug Targets 2008;9:869–
877.
34 Vilim V, Olejarova M, Machacek S, Gattero-
va J, Kraus VB, Pavelka K: Serum levels of
cartilage oligomeric matrix protein (COMP)
correlate with radiographic progression of
knee osteoarthritis. Osteoarthritis Cartilage
2002;10:707–713.
141.213.236.110 - 8/7/2013 8:38:36 PM
Univ. of Michigan, Taubman Med.Lib.
149
Downloaded by:
35 Kumm J, Tamm A, Lintrop M: Association
between ultrasonographic findings and
bone/cartilage biomarkers in patients with
early-stage knee osteoarthritis. Calcif Tissue
Int 2009;85:514–522.
36 Eckstein F, Cicuttini F, Raynauld JP, Water-
ton JC, Peterfy C: Magnetic resonance im-
aging (MRI) of articular cartilage in knee
osteoarthritis (OA): morphological assess-
ment. Osteoarthritis Cartilage 2006; 14
(suppl A):A46–A75.
37 Cranney A, Wells G, Willan A, et al: Meta-
analyses of therapies for postmenopausal os-
teoporosis. II. Meta-analysis of alendronate
for the treatment of postmenopausal women.
Endocr Rev 2002;23:508–516.
150 Gynecol Obstet Invest 2012;74:143–150
38 Lehmann HJ, Mouritzen U, Christgau S,
Cloos PA, Christiansen C: Effect of bisphos-
phonates on cartilage turnover assessed with
a newly developed assay for collagen type II
degradation products. Ann Rheum Dis
2002;61:530–533.
39 Buckland-Wright JC, Messent EA, Bingham
CO 3rd, Ward RJ, Tonkin C: A 2 year longi-
tudinal radiographic study examining the
effect of a bisphosphonate (risedronate)
upon subchondral bone loss in osteoarthrit-
ic knee patients. Rheumatology (Oxford)
2007;46:257–264.
40 Ding M, Danielsen CC, Hvid I: The effects of
bone remodeling inhibition by alendronate
on three-dimensional microarchitecture of
subchondral bone tissues in guinea pig pri-
mary osteoarthrosis. Calcif Tissue Int 2008;
82: 77–86.
41 Nishitani K, Shirai T, Kobayashi M, et al:
Positive effect of alendronate on subchon-
dral bone healing and subsequent cartilage
repair in a rabbit osteochondral defect mod-
el. Am J Sports Med 2009; 37(suppl 1):139S–
147S.
42 Ivaska KK, Hentunen TA, Vaaraniemi J,
Ylipahkala H, Pettersson K, Vaananen HK:
Release of intact and fragmented osteocalcin
molecules from bone matrix during bone re-
sorption in vitro. J Biol Chem 2004; 279:
18361–18369.
43 Couchourel D, Aubry I, Delalandre A, et al:
Altered mineralization of human osteoar-
thritic osteoblasts is attributable to abnor-
mal type I collagen production. Arthritis
Rheum 2009;60:1438–1450.
44 Sanchez C, Deberg MA, Bellahcnee A, et al:
Phenotypic characterization of osteoblasts
from the sclerotic zones of osteoarthritic
subchondral bone. Arthritis Rheum 2008;
58:442–455.
141.213.236.110 - 8/7/2013 8:38:36 PM
Univ. of Michigan, Taubman Med.Lib.
Seo /Yang /Lim /Jeon /Choi /Cho /Lee
Downloaded by: