|Year : 2016 | Volume
| Issue : 3 | Page : 131-136
Evaluation of serum undercarboxylated osteocalcin in premenopausal rheumatoid arthritis patients: its correlation with disease activity and bone mineral density
Heba A Esaily1, Abd El Samad Al Hewala2, Samar G Soliman1, Eman A Galbat1, Dalia H. Abo Al-Ela3
1 Physical Medicine and Rehabilitation Department, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Physical Medicine, Rheumatology and Rehabilitation Department, Faculty of Medicine, Zagazig University, Al Sharquia, Egypt
3 Clinical Pathology Department, Faculty of Medicine, Menoufia University, Menoufia, Egypt
|Date of Acceptance||20-Feb-2016|
|Date of Web Publication||7-Sep-2016|
Heba A Esaily
Physical Medicine and Rehabilitation department, Faculty of Medicine, Menoufia University, Menoufia 32111
Source of Support: None, Conflict of Interest: None
Background There is a definite role of vitamin K and undercarboxylated osteocalcin (ucOC) on bone mineral density (BMD) in rheumatoid arthritis (RA). Up to our knowledge, no other work has discussed the relationship between ucOC and BMD in premenopausal RA patients and its correlation with disease activity.
Patients and methods Sixty premenopausal RA female patients and 30 healthy premenopausal controls of matched age were included. All were subjected to clinical examination, laboratory investigations including serum level of ucOC, disease activity measurement using DAS-28 score, and BMD measurement using dual-energy X-ray absorptiometry.
Results The level of ucOC was significantly higher in patients with RA than in controls (P<0.001). BMD in patients was found to be significantly lower compared with controls in the spine, femoral neck, and distal radius areas. The most frequent osteoporotic site according to Z-score was the spine (16.7%), followed by the femoral neck (8.3%) and distal radius (6.7%). The most common commonest osteopenic site according to Z-score was the spine (31.7%), followed by the femoral neck (21.7%) and the distal radius (16.7%). Our work showed that ucOC level was found to be high in premenopausal RA patients with higher DAS values than in those with lower DAS value (P<0.001). In our work, BMD measured by means of dual-energy X-ray absorptiometry scan was found to be lower with higher DAS values and vice versa.
Conclusion Serum level of ucOC (which is a mirror of vitamin K deficiency) was found to be higher in premenopausal RA patients than controls and correlated positively with disease activity and inversely with BMD measurement.
Keywords: disease activity, osteoporosis, premenopause, rheumatoid arthritis, undercarboxylated osteocalcin
|How to cite this article:|
Esaily HA, Al Hewala AE, Soliman SG, Galbat EA, Al-Ela DA. Evaluation of serum undercarboxylated osteocalcin in premenopausal rheumatoid arthritis patients: its correlation with disease activity and bone mineral density. Egypt Rheumatol Rehabil 2016;43:131-6
|How to cite this URL:|
Esaily HA, Al Hewala AE, Soliman SG, Galbat EA, Al-Ela DA. Evaluation of serum undercarboxylated osteocalcin in premenopausal rheumatoid arthritis patients: its correlation with disease activity and bone mineral density. Egypt Rheumatol Rehabil [serial online] 2016 [cited 2019 Apr 19];43:131-6. Available from: http://www.err.eg.net/text.asp?2016/43/3/131/189822
| Introduction|| |
Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that causes chronic inflammation of the synovium with subsequent destruction and deformity of joints .
Osteoporosis results from a loss of bone mass (measured as bone density) as well as from a change in bone structure. Many factors will raise the risk of developing osteoporosis and breaking of the bone. Some risk factors can be changed, but others cannot be changed. Recognizing these risk factors is important to prevent this condition or treat it before it becomes worse .
Osteoporosis is more common in RA patients than in the general population. The prevalence of concurrent osteoporosis is 50%. Osteoporosis can cause pain, loss of height, and increases the risk for fractures after falling .
The chronic synovial inflammation in RA can promote osteoclastogenesis, leading directly to both focal and generalized bone loss and increased risk for fractures .
Vitamin K is a cofactor of γ-carboxylase, which converts three glutamic acid (Glu) residues in osteocalcin (OC) to γ-carboxyglutamic acid (Gla), and is thus essential for γ-carboxylation of OC. Without this modification, OC becomes undercarboxylated (ucOC), which lacks structural integrity and the ability to bind to the mineral hydroxyapatite. Vitamin K deficiency impairs γ-carboxylation of OC, resulting in high serum concentrations of ucOC .
| Patients and methods|| |
Sixty premenopausal patients diagnosed as having RA according the ACR/EULAR 2010 criteria  with age more than 16 years and disease duration more than 2 years were recruited from outpatient clinic of Physical Medicine and Rehabilitation Department, Faculty of Medicine, Menoufia University.
Postmenopausal RA female patients, RA male patients, patients suffering from serious cardiovascular and/or pulmonary disease, patients having an abnormal thyroid function or a serious infection, patients with hyperparathyroidism, patients with hepatic or renal dysfunction, those taking any drugs or hormones that affect bone metabolism (e.g. sex steroids, etc.), and those taking steroids during the last 6 months prior the study.
Thirty healthy premenopausal females of matched age who were free from earlier fractures, chronic diseases, and medications influencing bone metabolism (e.g. corticosteroids, anticonvulsants, thyroxine, etc.) were included as controls.
| Methods|| |
All patients were subjected to the following:
- Demographic data recording.
- Clinical assessment: Medical history (menstrual history, disease duration, information about medications such as disease modifying anti rheumatic drugs (DMARDs), antiresorptive drugs, corticosteroids, etc.). General examination (including chest, heart, and abdomen). Locomotor system examination.
- Disease activity Measurement: Disease Activity Score (DAS-28) with three variables (erythrocyte sedimentation rate, the number of swollen joints, and number of tender joins) was used .
- The level of disease activity was interpreted as follows: low: DAS-28≤3.2; moderate: 3.2<DAS-28≤5.1; high: DAS-28>5.1.
- A DAS<2.6 corresponds to being in remission according to the American Rheumatism Association (ARA) criteria .
- Laboratory investigations: Complete blood count , erythrocyte sedimentation rate , rheumatoid factor , anti-CCP level, C-reactive protein , and serum levels of ucOC.
- Radiographic assessment: Bone mineral density (BMD) was measured at the lumbar spine L2–L4, hip, and distal radius using a dual-energy X-ray absorptiometry (DEXA) equipment . BMD was expressed in SD from the mean of healthy age-matched and sex-matched people (the Z-score) and as the number of SD from the mean of healthy, young, sex-matched individuals (the T-score) using the WHO classification and the 2005 International Society for Clinical Densitometry (ISCD). A T-score of −2.5 or lower was defined as ‘osteoporosis’; osteopenia was defined as T-score less than −1 but greater than −2.5; normal was defined as T-score of at least −1 and a Z-score of −2.0 or lower in female patients before menopause was defined as ‘below the expected range for age’ .
The data collected were tabulated and analyzed using SPSS (Statistical Package for the Social Science software) statistical package version 20 on IBM compatible computer. Two types of statistics were performed. Descriptive statistics included percentage (%), range, mean (x), and SD, and for analytical statistics Student’s t-test, the Mann–Whitney test, and Fisher’s exact test were used. The difference was considered nonsignificant if P value was greater than 0.05, significant if P value was less than 0.05, and highly significant if P value was less than 0.001.
| Results|| |
In this work, the level of ucOC was significantly higher in RA patients than in controls (P<0.001) [Table 1] and higher in patients with osteoporosis than in those with osteopenia and normal BMD patients [Table 2] and [Figure 1]. BMD in patients was found to be significantly lower than that in controls at all sites (the spine, femoral neck, and distal radius areas). The most frequent osteoporotic site according to Z-score was the spine (16.7%), followed by the femoral neck (8.3%) and distal radius (6.7%). According to T-score, the most common osteoporotic site was the spine (13.3%). The most common osteopenic site according to Z-score of −1 or less was the spine (31.7%), followed by the femoral neck (21.7%) and the distal radius (16.7%) [Table 3]. Level of ucOC was found to be positively correlated with DAS score (P<0.001) [Table 4] and [Figure 2]. BMD measured using DEXA scan was found to be lower, with higher DAS values and vice versa, as shown in [Table 5].
|Table 1 Comparison between the studied groups of patients and controls as regards undercarboxylated osteocalcin (ng/ml)|
Click here to view
|Table 2 Comparison between osteoporotic female patients, osteopenic female patients, and individuals with normal bone mineral density as regards undercarboxylated osteocalcin (ng/ml)|
Click here to view
|Figure 1 Undercarboxylated osteocalcin (ucOC) levels in osteoporotic female patients, osteopenic female patients, and in individuals with normal dual-energy X-ray absorptiometry (DEXA) scan.|
Click here to view
|Table 3 Comparison between the studied groups of patients and controls as regards dual-energy X-ray absorptiometry parameters including number and percent|
Click here to view
|Table 4 Relationship between disease activity and undercarboxylated osteocalcin level (ng/ml) in studied group of patients (n=60)|
Click here to view
|Figure 2 Undercarboxylated osteocalcin (ucOC) level according to disease activity.|
Click here to view
|Table 5 Relationship between disease activity and dual-energy X-ray absorptiometry parameters in the studied group of patients (n=60)|
Click here to view
| Discussion|| |
RA is a chronic inflammatory autoimmune disease that causes chronic inflammation of the synovium, with subsequent destruction and deformity of the joints. Osteoporosis is more common in patients with RA than in the general population. Vitamin K is a cofactor of γ-carboxylase, which is essential for γ-carboxylation of OC. Without this modification, OC becomes ucOC, which lacks structural integrity and the ability to bind to the mineral hydroxyapatite, and the secreted OC can no longer be carboxylated. Vitamin K deficiency impairs γ-carboxylation of OC, resulting in high serum concentrations of ucOC.
This study revealed that the level of ucOC was significantly higher in patients with RA than in controls. This is in accordance with the findings of Sakai et al. , who showed that serum levels of ucOC were increased in higher state of bone turnover as indicated by biochemical markers, and vice versa.
No other researchers discussed ucOC in adult patients with RA. Van Summeren et al.  found that children with juvenile idiopathic arthritis (JIA) have a high ratio of ucOC/cOC, indicating low vitamin K status that was associated with low bone ultrasound parameters, whereas children with a high vitamin K status had markedly higher bone properties.
Moreover, Iwamoto et al.  found that serum ucOC is an index of vitamin K nutritional status in treating naïve postmenopausal osteoporotic women, and concluded that a high level of ucOC is a risk factor for osteoporotic fracture, which decreased with vitamin K intake.
Moreover, in this work, ucOC level was found to be positively correlated with disease activity in premenopausal RA patients.
To our knowledge, no other studies discussed the relationship between ucOC in premenopausal RA patients and DAS score.
In this work, BMD in patients was found to be significantly lower than that in controls in the spine, the femoral neck, and distal radius areas. The most frequent osteoporotic site according to Z-score was the spine (16.7%), followed by the femoral neck (8.3%) and distal radius (6.7%). The most common osteopenic site according to Z-score of −1 or less was the spine (31.7%), followed by the femoral neck (21.7%) and the distal radius (16.7%).
This is in accordance with the findings of Lee et al. , who found that the prevalence of osteoporosis in RA patients was 1.9 times higher than that in healthy individuals.
Moreover, Lodder and colleagues found that the frequencies of osteoporosis (T-score≤−2.5 SD) is 12.6 and 6.5% in the spine and femoral neck, respectively. Reduced bone mass or osteopenia was 20.7 and 18.9% in the spine and the femoral neck, respectively .
Laan and colleagues (2000) examined BMD in 97 patients with recent-onset RA and a mean disease duration of 30 months. Low bone mass (Z-score≤−1.0) was found in 32.0% of the patients in the lumbar spine and in 24.2% in the hip. They confirmed that low bone mass in comparison with healthy age-matched and sex-matched controls occurs frequently in patients with RA .
In another research, Haugeberg and colleagues (2000) studied a representative sample of 394 female RA patients with a mean disease duration of 13 years, using both T-scores and Z-scores. The prevalence of osteoporosis (T-scores≤−2.5) was 16.8% in the spine, 14.7% in the femoral neck, and 14.7% in the total hip. The prevalence of reduced bone mass (Z-scores≤−1.0) was greater than expected (15.9%) in the femoral neck (27.6%), the total hip (31.6), and the spine (19.6%) .
However, Hamalainen et al.  concluded that, according to bone mineral concentration, premenopausal RA women both with and without prednisolone treatment and controls lost bone statistically similarly.
Hui et al.  had followed up 130 healthy premenopausal white women for 1–9 years and found a significant decrease in femoral neck BMD over time.
In our work, BMD measured by means of DEXA scan was found to be lower with higher DAS values and vice versa.
This is in accordance with the findings of Lodder et al. , Shenstone et al. , and Gough et al. ; they concluded that patients with active disease lost more bone at the spine and hip compared with patients with inactive disease.
| Conclusion|| |
From the present study we concluded the following:
- Patients with RA are more susceptible to develop generalized osteoporosis compared with other population even if they are premenopausal.
- Serum level of ucOC is an indicator of BMD in premenopausal RA patients.
- Patients with high serum level of ucOC are more susceptible to osteoporosis compared with other patients.
- Patients with active RA disease are associated with higher levels of ucOC and lower BMD values.
- The most common sites of osteoporosis in premenopausal RA patients were in the lumbar spine (16.7%), followed by hip (8.3%) and distal radius (6.7%) according to Z-score.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest..
| References|| |
Chung SJ, Kwon YJ, Park MC, Park YB, Lee SK. The correlation between increased serum concentrations of interleukin-6 family cytokines and disease activity in rheumatoid arthritis patients. Yonsei Med J 2011; 52:113–120.
Sinnesael M, Boonen S, Claessens F, Gielen E, Vandersschueren D. Testosterone and the male skeleton: a dual mode of action. J Osteoporos 2011; 2:403–428.
Wijbrandts CA, Klaasen R, Dijkgraaf MG, Gerlag DM, van Eck-Smit BL, Tak PP. Bone mineral density in rheumatoid arthritis patients 1 year after adalimumab therapy: arrest of bone loss. Ann Rheum Dis 2009; 68:373–376.
Aizer J, Reed G, Onofrei A, Harrison MJ. Predictors of bone density testing in patients with rheumatoid arthritis. Rheumatol Int 2009; 29:897–905.
Koshihara Y, Hoshi K. Vitamin K2 enhances osteocalcin accumulation in the extracellular matrix of human osteoblasts in vitro. J Bone Miner Res 1997; 12:431438.
Funovits J, Aletaha D, Bykerk V, Combe B, Dougados M, Emery P et al.
American College of Rheumatology/European League Against Rheumatism classification criteria for rheumatoid arthritis: Methodological Report Phase I. Ann Rheum Dis 2010; 69:1589–1595.
Prevoo ML, van’t Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, van Riel PL. Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum 1995; 38:44–48.
Fransen J, Riel PL. The disease activity score and EULAR response criteria. Clinc Expr Rheuma 2005; 39:93–109.
Dacie GV, Lwis SM. Practical hematology. 6th ed. London: Churchill Livingstone; 1985. 33–35.
Westergren A. Diagnostic tests: the erythrocyte sedimentation rate range and limitations of the technique. Triangle 1957; 3:20–25.
Nikolaisen C, Rekvig OP, Nossent HC. Rheumatoid factor by laser nephelometry and Waaler-Rose assay: prognostic value in patients with recent-onset rheumatoid arthritis. Scand J Rheumatol 2005; 34:269–276.
Dominici R, Luraschi P, Franzini C. Measurement of C-reactive protein: two high sensitivity methods compared. J Clin Lab Anal 2004; 18:280–284.
Leslie WD, Adler RA, El-Hajj Fuleihan G, Hodsman AB, Kendler DL, McClung M et al.
Application of the1994 WHO classification to populations other than postmenopausal Caucasian women: the 2005 ISCD Official Positions. J Clin Densitom 2006; 9:22–30.
Sakai , Yoshitada H, Akira H, Teppei K, Yoshiko T, Chihiro S et al.
The serum level of undercarboxylated osteocalcin (ucOC) in patients with rheumatoid arthritis a high dose of predonisolone decrease the serum level of ucOC [abstract]. Arthritis Rheum 2010; 62:983–910.
Van Summeren MJ, Vermeer C, Engelbert RH, Schurgers LJ, Takken T, Fischer K, Kuis W. Extremes in vitamin K status of bone are related to bone ultrasound properties in children with juvenile idiopathic arthritis. Clin Exp Rheumatol 2008; 26:484–491.
Iwamoto J, Takada T, Sato Y. Vitamin K nutritional status and undercarboxylated osteocalcin in postmenopausal osteoporotic women treated with bisphosphonates. Asia Pac J Clin Nutr 2014; 23:256–262.
Lee SG, Park YE, Park SH, Kim TK, Choi HJ, Lee SJ et al.
Increased frequency of osteoporosis and BMD below the expected range for age among South Korean women with rheumatoid arthritis. Int J Rheum Dis 2012; 15:289–296.
Lodder MC, Haugeberg G, Lems WF, Uhlig T, Orstavik RE, Kostense P et al.
Radiological damage is associated with low BMD and vertebral deformities in rheumatoid arthritis. Accepted 18 January 2004 The Oslo-Truro-Amsterdam (OSTRA) collaborative study. Arthritis Rheum Arthritis Care Res 2003; 49:209–215.
Laan RF, Buijs WC, Verbeek AL, Draad MP, Corstens FH, van de Putte LB, Van Riel PL. Bone mineral density in patients with recent onset rheumatoid arthritis: influence of disease activity and functional capacity. Ann Rheum Dis 1993; 52:21–26.
Haugeberg G, Uhlig T, Falch JA, Halse JI, Kvien TK. Bone mineral density and frequency of osteoporosis in female patients with rheumatoid arthritis: results from 394 patients in the Oslo County Rheumatoid Arthritis register. Arthritis Rheum 2000; 43:522–530.
Hämäläinen H, Kaarela K, Kröger H, Kauppi M, Järvenpää S, Hakala M, Kotaniemi A. Changes in bone mineral density in premenopausal women with rheumatoid arthritis during a two-year follow-up. Joint Bone Spine 2007; 74:482–487.
Hui SL, Perkins AJ, Zhou L, Longcope C, Econs MJ, Peacock M et al.
Bone loss at the femoral neck in premenopausal white women: effects of weight change and sex-hormone levels. J Clin Endocrinol Metab 2002; 87:1539–1543.
Shenstone BD, Mahmoud A, Woodward R, Elvins D, Palmer R, Ring EF, Bhalla AK. Longitudinal bone mineral density changes in early rheumatoid arthritis. Br J Rheumatol 1994; 33:541–545.
Gough AK, Lilley J, Eyre S, Holder RL, Emery P. Generalised bone loss in patients with early rheumatoid arthritis. Lancet 1994; 344:23–27.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]