PDF - Advances in Clinical and Experimental Medicine

original papers
Adv Clin Exp Med 2013, 22, 2, 193–202
ISSN 1899–5276
© Copyright by Wroclaw Medical University
Agnieszka Matuszewska¹, A–D, Jacek Szechiński², A, E, F
Evaluation of Selected Bone Metabolism Markers
in Rheumatoid Arthritis Patients
Ocena wybranych markerów metabolizmu kostnego u chorych
na reumatoidalne zapalenie stawów
¹ Department of Pharmacology, Wroclaw Medical University, Poland
² Department and Clinic of Rheumatology and Internal Medicine, Wroclaw Medical University, Poland
A – research concept and design; B – collection and/or assembly of data; C – data analysis and interpretation;
D – writing the article; E – critical revision of the article; F – final approval of article; G – other
Abstract
Background. Rheumatoid arthritis (RA) is a chronic systemic disease of connective tissue characterized by progressive destructive arthritis associated with deformation and impairment of the function of the motor system. RA
patients more often present secondary osteoporosis and increased risk of fractures. The aetiology of the process
remains not fully understood. A significant role is played by proinflammatory cytokines being common mediators
of both inflammatory processes and bone remodelling.
Objectives. The purpose of the study was to evaluate the effect of activity of the inflammation and of applied therapy on osteogenesis marker concentrations in RA patients.
Material and Methods. Thirty six female patients with RA, confirmed according to ACR criteria, aged from 35 to
77 years were qualified into the study. A control group included 45 healthy women aged between 34 and 78 years.
Clinical evaluation (number of painful and swollen joints, DAS 28) and evaluation of RA laboratory activity (ESR,
CRP, blood cell count) and levels of selected bone metabolism markers (osteocalcin, PICP) and serum interleukin
1 levels were performed to carry out the study. X-rays of hands and densitometric scanning of the femoral bone
neck and spine were completed in order to assess the advancement of lesions in the bones.
Results. Osteocalcin and PICP levels were significantly lower in the RA groups compared to the control group
(2.51 ± 0.22 pg/mL vs. 18.65 ± 12.84 pg/mL, p < 0.0001; 0.292 ± 0.047 pg/mL vs. 0.829 ± 0.263 pg/mL, p < 0.0001
respectively). A statistically significant difference was also observed between the levels of osteocalcin and PICP in
both sub-groups of RA patients (DAS28 ≤ 5.1 and DAS28 > 5.1) and the control (osteocalcin 2.48 ± 0.23 pg/mL
vs. 18.65 ± 12.84 pg/mL, p < 0.0001; 2.52 ± 0.22 pg/mL vs. 18.65 ± 12.84 pg/mL, p < 0.0001 respectively and PICP
0.281 ± 0.053 pg/mL vs. 0.829 ± 0.263 pg/mL, p < 0.0001; 0.298 ± 0.044 pg/mL vs. 0.829 ± 0.263 pg/mL, p < 0.0001
respectively). No correlation was demonstrated between the levels of selected bone metabolism markers and the
therapy with methotrexate or cyclosporine.
Conclusions. Analysis of the obtained results confirms the presence of disorders of bone metabolism in RA
patients. A chronic inflammatory process favors the development of osteoporosis in RA patients. Reduced levels of
bone metabolism markers (osteocalcin, PICP) in the study group, compared to the control, may indicate a reduced
pace of osteogenesis in RA patients. No effect of therapy with methotrexate and cyclosporine on bone metabolism
in that group of patients was found (Adv Clin Exp Med 2013, 22, 2, 193–202).
Key words: rheumatoid arthritis, osteoporosis, bone metabolism, osteocalcin, women.
Streszczenie
Wprowadzenie. Reumatoidalne zapalenie stawów (r.z.s.) jest przewlekłą układową chorobą tkanki łącznej, która
charakteryzuje się postępującym destrukcyjnym zapaleniem stawów z deformacjami i upośledzeniem funkcji narządu ruchu. W tej grupie pacjentów częściej występuje osteoporoza wtórna i zwiększone ryzyko złamań. Patogeneza
tego zjawiska nie została do końca wyjaśniona. Istotną rolę pełnią cytokiny prozapalne, które są wspólnymi mediatorami procesów zapalenia i remodelingu kostnego.
194
A. Matuszewska, J. Szechiński
Cel pracy. Ocena wpływu aktywności zapalenia i stosowanej terapii na stężenie markerów kościotworzenia u chorych na reumatoidalne zapalenie stawów.
Materiał i metody. Do badania zakwalifikowano 36 kobiet chorych na r.z.s. wg kryteriów ACR w wieku 35–77 lat.
Grupę kontrolną stanowiło 45 zdrowych kobiet w wieku 34–78 lat. W pracy oceniano kliniczną (liczba bolesnych
i obrzękniętych stawów, DAS 28) i laboratoryjną aktywność r.z.s. (OB, CRP, morfologia), a także stężenie osteokalcyny, PICP, interleukiny 1 w surowicy. Aby określić zaawansowanie zmian w układzie kostnym, wykonywano RTG
rąk oraz badanie densytometryczne szyjki kości udowej i kręgosłupa.
Wyniki. Stężenie osteokalcyny i PICP było istotnie statystycznie mniejsze u chorych na r.z.s. niż w grupie kontrolnej (odpowiednio 2.51 ± 0.22 pg/mL vs 18.65 ± 12.84 pg/mL, p < 0.0001; 0.292 ± 0.047 pg/mL vs 0.829 ± 0.263 pg/
mL, p < 0.0001). Zaobserwowano także różnicę istotną statystycznie między stężeniem osteokalcyny, PICP w obu
podgrupach pacjentów z reumatoidalnym zapaleniem stawów (DAS28 ≤ 5.1 and DAS28 > 5.1) i grupą kontrolną
(odpowiednio osteokalcyna 2.48 ± 0.23 pg/mL vs 18.65 ± 12.84 pg/mL, p < 0.0001; 2.52 ± 0.22 pg/mL vs 18.65 ±
12.84 pg/mL, p < 0.0001 i odpowiednio PICP 0.281 ± 0.053 pg/mL vs 0.829 ± 0.263 pg/mL, p < 0.0001; 0.298 ±
0.044 pg/mL vs 0.829 ± 0.263 pg/mL, p < 0.0001). Nie wykazano zależności między stężeniem wybranych markerów
metabolizmu kostnego a stosowaniem metotreksatu, cyklosporyny.
Wnioski. Analiza uzyskanych wyników badań potwierdza istnienie zaburzeń metabolizmu kostnego u chorych na
reumatoidalne zapalenie stawów. Przewlekły proces zapalny jest czynnikiem nasilającym występowanie osteoporozy u chorych na r.z.s. Zmniejszone stężenia markerów metabolizmu kostnego (osteokalcyny, PICP) w grupie badanej w porównaniu z grupą kontrolną mogą świadczyć o spowolnieniu procesu tworzenia tkanki kostnej u chorych
na reumatoidalne zapalenie stawów. Nie stwierdzono wpływu terapii metotreksatem i cyklosporyną na metabolizm
tkanki kostnej w tej grupie pacjentów (Adv Clin Exp Med 2013, 22, 2, 193–202).
Słowa kluczowe: reumatoidalne zapalenie stawów, osteoporoza, metabolizm kostny, osteokalcyna, kobiety.
Rheumatoid arthritis (RA) is an autoimmune,
systemic disease of connective tissue. It is characterized by chronic synovitis accompanied by destruction of cartilage and osseous changes [1]. RA
is an important risk factor of osteoporosis and occurrence of fractures [2, 3]. Many authors describe
a significantly higher frequency of osteoporosis
and fractures in patients with RA in comparison
to a control group [4, 5]. The aetiology of progressive bone mass loss in RA patients is multi-factorial and remains obscure. Factors related to the
pathological process – activity of RA and applied
therapy – seem to be significant [6].
An active part in development of the inflammation in RA patients is played by cytokines secreted
by synoviocytes, macrophages, dendritic cells and
endothelial cells. An important role is played by,
among others, interleukin 1 (IL-1), interleukin 6
(IL-6) and tumor necrosis factor (TNFα). They are
the same time mediators of the inflammatory process and bone remodeling [7, 8]. Previous studies
also indicate a common basis for generalized bone
mass loss and local damage of joints, observed in
radiological examinations [9]. Many authors claim
that active inflammation even in the early stage of
RA influences bone mineral density [10, 11].
Bone is a living tissue, demonstrating metabolic activity. It undergoes constant remodeling that
ensures maintenance of the structural integrity of
the osseous system, repair of micro-damage and
exchange of its components with body fluids [12,
13]. Regardless of the primary cause, osteoporosis
is a result of a disturbed balance between the processes of resorption and formation of the osseous
tissue [14]. The intensity of these processes may
be evaluated using markers of bone metabolism.
These are protein structural fragments of bone,
enzymes or proteins released into the circulation
during the activity of osteoclasts and osteoblasts
[15]. The level of bone metabolism markers indicates the resultant activity of all processes of resorption and osteogenesis present at a given moment within the whole skeleton. Determination of
these markers may facilitate fracture prognosis or
evaluation of changes in bone mass during pharmacotherapy of osteoporosis [13].
Studies on the evaluation of bone marker levels in RA patients most often describe an increased
resorption of the bone tissue [16]. Increased levels
of some biochemical markers of bone resorption
are associated with a more rapid progression of
joint destruction in patients with early rheumatoid
arthritis and local bone erosion [17]. The formation process is unclear in RA patients. Levels of
bone formation markers have been variously reported to be normal, elevated or reduced [18].
This study tries to provide an answer to the
question if, and to what extent, the activity of RA
affects the levels of selected osteogenic markers
(osteocalcin, PICP).
Material and Methods
Characteristics of Study Groups
Thirty six women with RA diagnosed as per
the ACR criteria of 1987, hospitalized at the Clinic
of Rheumatology and Internal Diseases of the Academic Clinical Hospital in Wrocław, and in the
Department of Internal Diseases and Rheumatolo-
195
Bone Metabolism Markers in Rheumatoid Arthritis
gy in the PKP Hospital in Wrocław, aged between
35 and 77 years (mean age 58.2; standard deviation
s = 10.9, median value xmed = 56) were qualified for
the study. The characteristic of the patients with
RA are presented in Table 1.
A control group included 45 healthy women
aged between 34 and 78 (mean age 56.4; standard
deviation s = 10.3; median value xmed = 58) recruited among blood donors, healthcare professionals
and their families.
Scope of Tests
Evaluation of the clinical and laboratory activity of the disease and determination of the levels of
selected bone metabolism markers in RA patients
were performed.
The DAS28 index, commonly used in clinical
practice and in studies of the efficacy of a therapy
activity, was used for evaluation of rheumatoid arthritis intensity. The index involves both edematous joints (physical examination by a physician
– objective evaluation), intensity of pain of joints
during the last week (patient’s subjective evaluation) and a laboratory parameter of activity of the
disease – ESR (objective evaluation). A high activ-
ity of RA is reflected by a DAS28 score over 5.1.
This value was adopted as a limiting one (according to EULAR guidelines).
Markers of osteogenesis were assayed – osteocalcin (hOST EASIA Kit KAP 1381, BioSource,
normal range: 5–25 ng/mL), PICP (Procollagen
Type I C-Peptide EIA Kit, Takara Bio Inc, normal
range: 0.01–0.64 pg/mL) and interleukin 1 (Quantikine Human IL-1β Immunoassay, R&D Systems
Inc, Minneapolis, MN, USA, normal range: up to
3.9 pg/mL).
Imaging techniques were used to evaluate
changes occurring in the osseous system: X-ray
and densitometric scanning (DXA) of the proximal epiphysis of the femur and lumbar spine. Radiological examination of hands was performed,
because of the occurrence of changes characteristic for RA in that area, and to evaluate the stage of
progression of the disease (acc. to the Steinbrocker
classification).
The study obtained permission from the Bioethical Commission operating by the Wroclaw
Medical University in Wrocław. The majority of
the tests were financed from funds granted by
the Committee of Scientific Research (N 402 048
32/1494; GR – 672/2007).
Table 1. Characteristic of the 36 patients with RA
Tabela 1. Charakterystyka 36 pacjentów z r.z.s.
Demographic (Czynniki demograficzne)
Female (Kobiety) [%]
Age – years (Wiek – lata)
Post-menopausal (Odsetek kobiet po menopauzie) [%]
Body mass index (Wskaźnik masy ciała) [kg/m²]
Disease (Choroba)
Rheumatoid arthritis duration – years (Czas trwania reumatoidalnego zapalenia stawów – lata)
Rheumatoid factor-positive (Dodatni czynnik reumatoidalny) [%]
Disease activity score comprising 28 joints (Wskaźnik aktywności choroby DAS28)
Visual analogue score (Wizualna skala analogowa bólu) [mm]
Steinbrocker functional class – % in class IV (Zaawansowanie zmian kostnych wg Steinbrockera – % w klasie IV)
Standardized BMD hip (Standaryzowane BMD biodra) [g/cm²]
Standardized BMD spine (Standaryzowane BMD kręgosłupa) [g/cm²]
10-year risk fracture FRAX (10-letnie ryzyko złamań FRAX) [%]
100
58.2 (35–77)
77.8
25.8 (18–35)
13.3 (1–35)
86.1
5.8 (2.6–8.4)
60.9 (10–100)
41.7
827.3 (444.5–1334.4)
957.9 (614.0–1323.9)
21.8 (8–61)
Laboratory investigation (Badania laboratoryjne)
Erythrocyte sedimentation rate (Odczyn Biernackiego) [mm/h]
C-reactive protein (Białko C-reaktywne) [mg/dL]
Leucocyte (Leukocyty) [tys./mm³]
Hemoglobin (Hemoglobina) [g/dL]
Thrombocyte (Płytki krwi) [tys./mm³]
Calcium in serum (Wapń całkowity we krwi) [mg/dL]
42 (7–112)
20.2 (3.0–80.7)
8.5 (4.2–16.4)
12.0 (8.9–14.5)
283 (82–500)
9.4 (8.4–11.2)
Medication (Leki)
Methotrexate use present (Odsetek chorych obecnie stosujących metotreksat) [%]
Cyclosporine use present (Odsetek chorych obecnie stosujących cyklosporynę) [%]
Steroid use present (Odsetek chorych obecnie stosujących steroidoterapię) [%]
Duration of steroid use – years (Czas trwania steroidoterapii – lata)
58.3
25
75
5.4 (0–19)
196
A. Matuszewska, J. Szechiński
Table 2. Analysis of levels of individual markers of bone metabolism in relation to use of methotrexate therapy
Tabela 2. Analiza stężeń wybranych markerów obrotu kostnego w zależności od stosowania w terapii metotreksatu
Analyzed characteristics
(Analizowana cecha)
Current methotrexate user
(Aktualna terapia metotreksatem)
yes
Significance level
(Poziom istotności)
no
Methotrexat (Metotreksat) (ng/mL)
0.152
Number (Liczebność) N
21
15
Mean (Średnia)
2.5514
2.4390
Standard deviation (Odchylenie standardowe)
0.1662
0.2818
PICP (pg/mL)
0.244
Number (Liczebność) N
21
15
Mean (Średnia)
0.2868
0.3004
Standard deviation (Odchylenie standardowe)
0.0525
0.0386
Table 3. Analysis of levels of individual markers of bone metabolism in relation to use of cyclosporine therapy
Tabela 3. Analiza stężeń wybranych markerów obrotu kostnego w zależności od stosowania w terapii cyklosporyny
Analyzed characteristics
(Analizowana cecha)
Current cyclosporine user
(Aktualna terapia cyklosporyną)
yes
Significance level
(Poziom istotności)
no
Osteocalcin (Osteokalcyna) (ng/mL)
0.731
Number (Liczebność) N
9
27
Mean (Średnia)
2.521778
2.498778
Standard deviation (Odchylenie standardowe)
0.114413
0.253167
PICP (pg/mL)
0.869
Number (Liczebność) N
9
27
Mean (Średnia)
0.2907
0.2931
Standard deviation (Odchylenie standardowe)
0.0490
0.0474
Statistical Analysis
The results are presented as mean ± standard
deviation. Normality of distribution was verified
using a Shapiro-Wilk normality test. If normal distribution was proved, a comparison of the groups
was performed with a parametric Student t-test. If
the distribution of markers was significantly different from normal distribution, a non-parametric Mann-Whitney U test was used for comparison. The results were treated as significant if the
p value was less than 0.05. The statistical analysis
was performed with STATISTICA 9 AXFP104B401313AR-K, Wroclaw Medical University, Poland.
Results
Comparative Evaluation of
Levels of Bone Metabolism
Markers in RA Patients and in
the Control Group
Osteocalcin and PICP levels were significantly
lower in the RA groups compared to the control
group (2.51 ± 0.22 pg/mL vs. 18.65 ± 12.84 pg/mL,
p < 0.0001; 0.292 ± 0.047 pg/mL vs. 0.829 ± 0.263
pg/mL, p < 0.0001). Moreover, a higher concentration of interleukin 1 in the serum of RA patients
was found, compared to the values determined in
197
Bone Metabolism Markers in Rheumatoid Arthritis
25,00
0,90
0,80
0,70
PICP pg/mL
osteocalcin mg/mL
20,00
15,00
10,00
0,60
0,50
0,40
0,30
0,20
5,00
0,10
0,00
control group
17.92
0,00
RA group
2.5
Fig. 1. Mean osteocalcin level in control and study
groups
Ryc. 1. Średnie stężenie osteokalcyny w grupach kontrolnej i badanej
IL-1β pg/mL
2,00
1,50
1,00
0,50
control group
0.83
RA group
2.6
Fig. 3. Mean IL-1β level in control and study groups
Ryc. 3. Średnie stężenie IL-1β w grupach kontrolnej
i badanej
Kruskal-Wallis test
p < 0.0001, H (2, N = 76) = 50.71
35
30
25
osteocalcin (ng/mL)
Fig. 2. Mean of PICP level in control and study groups
Ryc. 2. Średnie stężenie PICP w grupach kontrolnej
i badanej
Evaluation of Levels of Bone
Metabolism Markers in Relation
to RA Activity Measured
with DAS28
2,50
In the study, a statistically significant difference was observed between the levels of osteocalcin and PICP in both sub-groups of RA patients
(DAS28 ≤ 5.1 and DAS28 > 5.1) and the control
(Osteocalcin 2.48 ± 0.23 pg/mL vs. 18.65 ± 12.84
pg/mL, p < 0.0001; 2.52 ± 0.22 pg/mL vs. 18.65
± 12.84 pg/mL, p < 0.0001 respectively and PICP
0.281 ± 0.053 pg/mL vs. 0.829 ± 0.263 pg/mL, p <
0.0001; 0.298 ± 0.044 pg/mL vs. 0.829 ± 0.263 pg/
mL, p < 0.0001 respectively). However, no dif-
Fig. 4. Comparison of osteocalcin levels
in the subgroup of rheumatoid arthritis
patients: DAS28 > 5.1, DAS28 ≤ 5.1 and
control group and the result of KruskalWallis test
Ryc. 4. Porównanie stężenia osteokalcyny
w podgrupach kobiet chorych na reumatoidalne zapalenie stawów: DAS28 >
5.1, DAS28 < 5.1 i grupie kontrolnej oraz
wynik testu Kruskala-Wallisa
20
15
10
5
0
RA group
0.29
the control group (2.60 ± 0.63 pg/mL vs. 0.83 ±
0.57 pg/mL, p < 0.0001).
3,00
0,00
control group
0.83
Średnia
Średnia±Błąd std
Średnia±Odch.std
DAS28 > 5.1
DAS28 < 5.1
groups
control group
198
A. Matuszewska, J. Szechiński
Kruskal-Wallis test
p <0.0001, H (2, N = 76) = 56.37
1,6
Fig. 5. Comparison of PICP levels in
the subgroup of rheumatoid arthritis
patients: DAS28 > 5.1, DAS28 < 5.1 and
control group and the result of KruskalWallis test
1,4
PICP (pg/mL)
1,2
Ryc. 5. Porównanie stężenia PICP
w podgrupach kobiet chorych na reumatoidalne zapalenie stawów: DAS28 > 5.1,
DAS28 < 5.1 i grupie kontrolnej oraz
wynik testu Kruskala-Wallisa
1,0
0,8
0,6
0,4
0,2
0,0
Mediana
25%-75%
Min-Maks
DAS28 > 5.1
DAS28 < 5.1
control group
groups
U Mann-Whitney test
p = 0.034, Z = -2.112
20
Fig. 6. Comparison of duration of glucocorticosteroids treatment in the subgroups with various duration of RA and
the result of U Mann-Whitney test
duration of glucocorticosteroids treatment
18
16
Ryc. 6. Porównanie czasu stosowania
glikokortykosteroidów w podgrupach
różniących się czasem trwania choroby
oraz wynik testu U Manna-Whitneya
14
12
10
8
6
4
2
Mediana
25%-75%
Min-Maks
0
-2
up to 10 years
more than 10 years
RA duration
ferences were observed between both subgroups.
The results are presented in Figs. 4 and 5.
The sub-groups of women presenting different
indexes of activity of the disease (group I: DAS28
≤ 5.1, group II: DAS28 > 5.1) demonstrated statistically significant differences in relation to the
following:
– the ratio of patients with positive RF – latex
(66.7% vs. 95.8%, p = 0.020),
– the average time of therapy with glucocorticosteroids (7.8 ± 5.3 years vs. 4.3 ± 3.5 years,
p = 0.046).
No significant difference between the other
analyzed characteristics (e.g. age, number of postmenopausal women, years after menopause, duration of RA, advancement of RA acc. to X-ray scan-
ning, 10-year risk of fracture) analyzed in relation
to the DAS28 value was found.
Evaluation of Levels of Bone
Metabolism Markers in Relation
to the Therapy of RA
No statistically significant relationship was
found between the level of osteocalcin and PICP
and the use of methotrexate or cyclosporine (Tables 2 and 3). Analysis of the a.m. markers of bone
metabolism showed no statistically significant differences between the users and non-users of steroid therapy. However, a higher PICP level was
found in women treated with glucocorticosteroids
199
Bone Metabolism Markers in Rheumatoid Arthritis
U Mann-Whitney test
p = 0.007, Z = 2.674
standardised BMD in DXA of the neck of the femur
1400
Fig. 7. Comparison of standardised BMD
in DXA of the neck of the femur in the
subgroups with various duration of RA
and the result of U Mann-Whitney test
1300
1200
Ryc. 7. Porównanie standaryzowanej
BMD w DXA szyjki kości udowej
w podgrupach różniących się czasem
trwania choroby oraz wynik testu
U Manna-Whitneya
1100
1000
900
800
700
600
Mediana
25%-75%
Min-Maks
500
400
up to 10 years
more than 10 years
RA duration
U Mann-Whitney test
p = 0.025, Z = 2.234
Fig. 8. Comparison of duration of postmenopausal period in the subgroups
women with various duration of RA and
the result of U Mann-Whitney test
35
duration of postmenopausal period
30
25
Ryc. 8. Porównanie czasu trwania okresu
pomenopauzalnego w podgrupach kobiet
różniących się czasem trwania RZS oraz
wynik testu U Manna-Whitneya
20
15
10
5
Mediana
25%-75%
Min-Maks
0
-5
more than 10 years
up to 10 years
RA duration
(GKS) for over 12 months compared to women
treated for a shorter period of time. No correlation
was observed between the accumulated GCS dose
and the level of PICP and osteocalcin.
Evaluation of Levels of Bone
Metabolism Markers in Relation
to Duration of RA
No statistically significant differences were observed between the subgroups with various duration of the disease (group I – up to 10 years, group
II – 11 years and longer) in relation to age, number of post-menopausal women, number of lowenergy fractures, number of patients with a sero-
positive form of RA and the dose of currently-used
steroid therapy.
Statistically significant differences between the
subgroups of women with various durations of RA
(group I – up to 10 years, group II – 11 years and longer) were observed for the following characteristics:
– duration of GKS treatment (Fig. 6), (3.7 ±
2.8 years vs. 7.2 ± 5.1 years, p = 0.034),
– standardized BMD in DXA of the neck of
the femur (Fig. 7), (914.9 ± 194.9 vs. 659.1 ± 247.3,
p = 0.007),
– duration of postmenopausal period (Fig. 8),
(5.5 ± 7.1 years vs. 15.7 ± 7.8 years, p = 0.025).
Moreover, a difference was observed in the
number of patients in the compared subgroups in
relation to the stage of advancement of the disease
200
A. Matuszewska, J. Szechiński
as revealed by an X-ray. In women suffering from
RA for up to 10 years, the 2nd stage of advancement
acc. to the Steinbrocker classification predominated, and in women suffering from RA for 11 years
or longer – the 4th stage (p = 0.011).
Discussion
Osteoporosis is a significant complication of
rheumatoid arthritis, having an additional negative effect on patients’ quality of life. Progressive
bone mass reduction is a result of numerous factors. Some of them are known, and their effect is
confirmed. They are old age, gender, postmenopausal period of life, unbalanced diet or tobacco
smoking. However, there are still doubts whether
osteoporosis depends on the activity of RA, its duration and applied therapy.
Studies completed by numerous authors have
demonstrated a significantly higher prevalence of
osteoporosis in the group of RA patients compared
to healthy controls [4, 5]. A statistically significant
relationship was found between the development
of osteoporosis and the time of advancement of
the disease [19, 20]. Also in this study, a more
frequent osteoporosis prevalence was observed in
patients with a long-lasting RA.
According to many authors, the activity of RA
is the main factor deciding the level of intensity
of generalized osteoporosis in that pathology [21].
Excessive production of proinflammatory cytokines, including IL-1, TNF-alpha and IL-6, plays an
important role in the stimulation of the catabolic
processes of the osseous tissue, leading to its destruction [22]. Their increased levels compared to
the control group were found in RA patients [23].
This observation is also confirmed by the results of
this study. In RA patients, increased CRP level and
ESR value were associated with an intensified loss
of BMD in hand bones [24]. Franck et al. [5] demonstrated significantly lower BMD values of the
femoral bone neck in patients with elevated CRP
(CRP > 5 mg/L). However, Hafez et al. [25] observed an increased DAS28 index in patients with
early RA meeting the densitometric criteria of osteoporosis compared to patients with a regular
mineral density of bones or osteopenia, although
the difference was not statistically significant.
Secondary osteoporosis develops in RA patients as a result of a disturbed homeostasis of
bone metabolism. Numerous authors point out
the intensification of the process of resorption of
osseous tissue [5, 26]. The process of the formation
of osseous tissue has not been precisely understood
yet. There are only a few studies focusing on that
phenomenon. Wisłowska et al. [20] did not find
a correlation between the intensification of RA activity measured by the DAS28 index and the level
of a marker of osteogenesis: procollagen type I Nterminal propeptide (PINP). This study also failed
to observe a relationship between the DAS28 index and levels of osteocalcin and PICP. However,
in both subgroups of patients (DAS28 ≤ 5.1 and
DAS28 > 5.1), statistically significantly lower levels
of osteocalcin and PICP were found compared to
the control group (p < 0.0001). Dequeker [10] suggested that the activity of RA may only be reflected
by periarticular osteoporosis, and only during the
early stage of the disease, because only there and
then does the condition depend solely on the active
phase of inflammation. That opinion seems to explain the results presented here, as patients suffering from RA for multiple years had been included.
Despite the fact that momentary activity did not
correlate with the markers of bone metabolism,
repeated episodes of exacerbation affected advancement of the disease and associated bone loss.
Decreased levels of the bone metabolism markers
osteocalcin and PICP in the study group compared
to the control group may reflect inhibition of the
formation of osseous tissue in RA patients.
There is an ongoing discussion in the literature on the effect of the therapy of RA on the development of secondary osteoporosis. Methotrexate (MTX) is the main drug used in this group of
patients. MTX is characterized by a significant efficacy in the inhibition of structural damage [27].
Studies on animal models indicate that high doses
of the drug may damage bone progenitor cells,
inhibit proliferation of osteoblasts and increase
resorption [28]. Bone mass decrease was observed
in methotrexate-treated oncological patients [29].
However, in the case of chemotherapy, the doses
of the drug are much higher than the doses used in
rheumatology. The therapy of RA usually involves
administration of 7.5–25 mg/week of MTX. Multiple studies indicate that the use of methotrexate
in RA patients may have no unfavorable effects on
the osseous tissue, because the drug reduces bone
mass loss associated with an active, uncontrolled
inflammatory process. Torikari et al. [30] found
a statistically significant reduction of levels of bone
resorption markers (amino-terminal collagen
crosslinks (NTX), desoxypyridinoline) in methotrexate-treated RA patients. However, no statistically significant differences in the levels of alkaline
phosphatase (BAP) as a marker of osteogenesis
were found. The results presented here also do not
confirm an unfavorable effect of methotrexate on
bone metabolism measured with the markers of
osteogenesis. No statistically significant correlation was observed between the level of osteocalcin
and PICP and the therapy with that drug.
Bone Metabolism Markers in Rheumatoid Arthritis
Literature data indicates that the administration
of cyclosporine may affect osteoblasts and osteoclasts,
leading to a prevalence of the processes of resorption
over osteogenesis, and therefore to more pronounced
bone mass loss [31]. Previous clinical research indicating an unfavorable effect of cyclosporine on bone
mineral density and risk of fractures were based on
large doses of the drug used in transplantology [32].
It is believed nowadays that a dose of 5 mg/kg/day or
less of cyclosporine used in RA has no unfavorable
effects on bone metabolism [33]. This observation is
confirmed by the results of this study. No statistically
significant correlation was observed between the level
of osteocalcin and PICP and the use of cyclosporine
at a dose of 2–3.5 mg/kg/day. Also Mazzantini et al.
[34], comparing patients treated with CsA and patients receiving no treatment with the drug noted
that the mean values of the T-score in densitometric scanning of the neck of the femur or spine were
comparable. The ratio of patients with osteoporosis
was also not different in those groups. However, analyzing the duration of the therapy, a lower mineral
density of bones was observed in patients treated
with cyclosporine for over 24 months, than in those
treated for shorter period of time.
Glucocorticosteroids (GCS) exert a confirmed
effect on the osseous tissue. There are numerous papers describing the intensification of the process of
resorption and progressive bone mass loss, as well as
the development of osteoporosis as a complication
of long-term steroid therapy. On the other hand,
however, an important role in the optimal control of the inflammatory process in RA patients is
201
stressed. Some authors indicate that along with the
use of DMARDs for the achievement of remission,
a short-term therapy with low doses of glucocorticosteroids may be also favorable [35]. Korczowska
et al. [36] found no statistical differences between
the level of osteocalcin in RA patients and in the
control group, with higher concentration of procollagen type I C-terminal propeptide in the group
of RA patients. Following a 12-month follow-up,
the authors demonstrated, however, a statistically
significant reduction of osteogenic markers in RA
patients who had glucocorticosteroids introduced
for the first time. Also Engwall et al. [37] observed
a reduced level of the marker of osteogenesis (procollagen type I N-terminal propeptide) in patients
with early RA treated with prednisone. The results
of this study indicate no relationship between the
use of GCS and the level of osteocalcin and PICP.
This observation may be a result of the fact that the
highest remodeling takes place during the first 6–12
months of steroid therapy [38], and a result of the
selection of the study group – a significant majority
of qualified women used steroids for periods longer
than 12 months years.
Summing up the results of the above study,
the presence of a disturbance in bone metabolism
in RA patients has to be confirmed. A chronic
inflammatory process is a factor intensifying the
development of osteoporosis in RA patients. Reduced levels of bone metabolism markers (osteocalcin, PICP) in the study group compared to the
control may reflect a reduced intensity of the process of osteogenesis in RA patients.
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Address for correspondence:
Agnieszka Matuszewska
Department of Pharmacology
Wroclaw Medical University
J. Mikulicza-Radeckiego 2
50-345 Wrocław
Poland
Tel.: +48 71 784 14 38
E-mail: [email protected]
Conflict of interest: None declared
Received: 24.09.2012
Revised: 8.01.2013
Accepted: 18.04.2013