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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 4  |  Issue : 3  |  Page : 82-89

Sclerostin level in rheumatoid arthritis patients and its relationship to disease severity and bone mineral density


1 Department of Internal Medicine, Rheumatology, and Clinical Immunology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
2 Department of Radiodiagnosis, Faculty of Medicine, Alexandria University, Alexandria, Egypt
3 Department of Clinical and Chemical Pathology, Faculty of Medicine, Alexandria University, Alexandria, Egypt

Date of Submission06-Feb-2019
Date of Acceptance15-Apr-2019
Date of Web Publication3-Oct-2019

Correspondence Address:
Assisstant Professor Abdel Ghani Eman
Internal Medicine, Rheumatology and Clinical Immunology Unit, Faculty Of Medicine, University Of Alexandria, 25, Talaat Harb Street, El-Atarrine, Alexandria
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ejode.ejode_3_19

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  Abstract 


Background Bone loss in rheumatoid arthritis is caused by increased bone resorption without increasing bone formation. The Wnt pathway is important in the control of bone formation through the regulation of osteoblast activity. Sclerostin is an important regulator of the Wnt pathway by blocking Wnt binding to its receptor and thereby , inhibiting bone formation.
Aim Of The Work was to correlate the relation between level of serum sclerostin and bone mineral density with disease severity in rheumatoid arthritis patients.
Subjects The study was conducted on 50 subjects divided into two groups: Group I : Thirty patients of rheumatoid arthritis subjects diagnosed according to 2010 ACR / EULAR diagnostic criteria. Group II : Twenty persons as a control group.
Methods All patients were subjected to ; thorough medical history taking, DAS -28, disability Index, complete blood count (CBC), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), RF, antinuclear antibody (ANA), Anti-CCP Antibodies, Human Sclerostin levels using ELISA technique, Plain X- ray on both hands and feets, U/S on both hands, and (DEXA) scan.
Results There was a statistical significant difference between the two studied groups regarding the age, gender, sclerostin level, and DAS-28 (P>0.05).
Conclusion Most of patients were under treatment with disease modifying anti-rheumatic drugs (DMARDs) as methotrexate, fracture risk was not assessed, and measurements for renal function were not measured. However, it is possible that circulating sclerostin levels may not reflect changes of sclerostin at a local level. Despite the many questions that remain, pre-clinical studies and clinical trial results would imply that sclerostin antibodies will emerge as a dominant first- line treatment in the management of osteoporosis.

Keywords: bone mineral density, rheumatoid arthritis, sclerostin, wnt pathway


How to cite this article:
Mona AM, Barakat B, Mona A, Eman AG, Heba B. Sclerostin level in rheumatoid arthritis patients and its relationship to disease severity and bone mineral density. Egypt J Obes Diabetes Endocrinol 2018;4:82-9

How to cite this URL:
Mona AM, Barakat B, Mona A, Eman AG, Heba B. Sclerostin level in rheumatoid arthritis patients and its relationship to disease severity and bone mineral density. Egypt J Obes Diabetes Endocrinol [serial online] 2018 [cited 2019 Oct 15];4:82-9. Available from: http://www.ejode.eg.net/text.asp?2018/4/3/82/268514




  Introduction Top


Rheumatoid arthritis (RA) is an autoimmune disease affecting ∼1% of the population worldwide [1]. It is characterized by chronic and symmetric inflammation of the synovial joints, leading to joint destruction, chronic joint pain, loss of function, and disability [2]. RA may also result in bone complications such as peri-articular bone loss, bone erosions, and generalized osteoporosis [3],[4],[5]. RA is highly associated with significant bone mineral density (BMD) loss in femoral neck, lumbar spine, and generalized osteoporosis with an increased risk of fractures [6],[7],[8],[9]. Multiple factors have been suggested to be involved in the higher prevalence of osteoporosis in patients with RA, with the osteoblast − osteoclast axis severely affected. This disruption occurs owing to the ongoing inflammatory process, which enhances osteoclast formation, immobility, and chronic treatment with corticosteroids [10],[11]. The inherent risk factors for osteoporosis are aging and female sex [12]. Sclerostin (SOST) affects bone remodeling in both the normal and pathological stages [13],[14]. SOST is a glycoprotein product of the SOST gene and is highly expressed in embedding bone cells such as osteocytes, chondrocytes, and cementocytes [15],[16],[17]. Several Wnt family members seem to be involved in the modulation of the inflammatory response during rheumatoid activity. Serum SOST levels are being investigated in various metabolic bone diseases. The Wnt pathway has been shown to be important for the differentiation of osteoblasts from mesenchymal lineage precursors, and from endogenous Wnt inhibitors such as Dickkopf-1 (DKK-1), SOST, and secreted frizzled-related proteins. SOST might have important roles of osteoclast dysregulation in RA by inhibiting the Wnt/B-catenin canonical signaling pathway and binding to the low signaling lipoprotein receptor LRP-5/LRP-6, leading to decreased osteo-blastogenesis and osteoblast activity, and thereby decreasing bone formation [18],[19]. SOST binds to bone morphogenic proteins as well as to LRP-5 and LRP-6, thus antagonizing bone morphogenic protein and Wnt signaling and enhancing osteoblast formation. As, SOST levels are decreased in primary hyperparathyroidism and elevated in hypoparathyroidism, parathyroid hormone is thought to be a regulatory factor for SOST. On the contrary, high serum SOST level in postmenopausal women is a risk factor for fractures. Several clinical studies have shown a significant increase of SOST levels with age and after menopause, suggesting that serum SOST may be associated with aging and menopause-induced bone loss [14],[20],[21]. Although glucocorticoid-induced osteoporosis and diabetes are both diseases that reduce bone formation, serum SOST levels have been reported to be decreased in the former and elevated in the latter. Serum SOST levels are correlated with renal function and increase with reduction in renal function, suggesting the difference in the effect of SOST in these diseases [22]. Serum SOST may be a new index of bone assessment that differs from BMD markers and other bone metabolic markers [23].


  Aim Top


The aim of the work was to correlate the relation between level of serum SOST and BMD with disease severity in patients with RA.


  Patients and methods Top


The study was conducted on 50 patients recruited from Alexandria Main University Hospital, Egypt. The 50 patients were divided into two groups: group I had 30 cases of RA diagnosed according to ACR/EULAR 2010 diagnostic criteria [24], and group II had 20 age-matched and sex-matched persons as a control group.

Inclusion criteria

Patients with RA were included.

Exclusion criteria

Patients with other connective tissue diseases as systemic lupus erythematosus, systemic sclerosis, and diabetes mellitus, patients on steroids, and patients with metabolic bone diseases were excluded.


  Methods Top


All patients were subjected to the following: (a) thorough medical history taking, with specific stress on disease duration, duration of morning stiffness, number of swollen joints, and number of tender joints; (b) full clinical examination with specific stress on musculo-skeletal system examination; (c) determination of disease activity score by Disease Activity Score (DAS)-28 [25] and disability index (HAQ-DI) [26]; (d) laboratory tests, including complete blood count (CBC) [27], acute-phase reactants [erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)] [28], rheumatoid factor [29], antinuclear antibody (ANA) titer using ELISA [30], anticitrullinated protein antibody using ELISA [31], and human SOST levels using ELISA technique [32]; (e) plain radiograph on both hands; and (f) ultrasound (US) for each hand and wrist for detection of early bone erosions (including navicular, and lunate bones) and six joints [five metatarsophalangeal joints (MTPJs) and interphalangeal joints (IPJ)] for each foot.

The Svd H score defines erosions as follows: 0=no erosions (normal), 1=minor of discrete erosions, 2–3=larger erosions according to surface area involved, 4=erosions extending over the middle of the bone, 5=complete collapse, and 6=BMD assessment by dual-energy X-ray absorptiometry (DEXA) scan.


  Results Top


[Table 1] shows comparison between the two studied groups according to characteristics. There was a statistically significant difference between the two studied groups regarding age. [Table 2] shows distribution of the studied patients regarding the disease severity indices (DAS-28 and HAQ-DI). [Table 3] shows relation between DAS-28 and demographic data of the patients group. [Table 4] shows relation between HAQ score and demographic data of patients group. [Table 5] shows distribution of the studied patient group regarding the clinical and laboratory parameters of disease activity. [Table 6] shows distribution of the studied patients group regarding DEXA scan. [Table 7] shows relation between radiograph findings and DEXA scan, DAS-28 score, and HAQ score. [Table 8] shows relation between the results of US and DEXA scan, DAS-28, HAQ score, and radiograph in RA group. [Table 9] shows comparison between the two studied groups regarding the SOST. There was a statistically significant difference between the patient group and the control group regarding the SOST (P<0.05). [Table 10] shows the relation between SOST and demographic data of patients group. There was a statistically significant relation regarding sex (P<0.05). [Table 11] shows the correlation between SOST and DAS-28, HAQ score, and US. [Table 12] shows the correlation between SOST and haemoglobin (Hb%), ESR first hour, and second hour. [Table 13] shows the relation between the results of DEXA scan and DAS-28, SOST, and HAQ score in the patient group. There was a statistically significant difference regarding DAS-28 (P>0.05). [Table 14] shows the relation between SOST and clinical and laboratory parameters of disease activity in the patients group. [Table 15] shows the relation between the results of US and DEXA scan, SOST, DAS-28 score, HAQ score, and radiograph in RA group.
Table 1 Comparison between the two studied groups according to characteristics

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Table 2 Distribution of the studied patients regarding the disease severity indices

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Table 3 Relation between Disease Activity Score-28 and demographic data of the patient group

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Table 4 Relation between HAQ score and demographic data of the patient group

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Table 5 Distribution of the studied patient group regarding the clinical and laboratory parameters

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Table 6 Distribution of the studied patient group regarding dual-energy X-ray absorptiometry scan

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Table 7 Relation between X-ray findings and dual-energy X-ray absorptiometry, Disease Activity Score-28, and HAQ

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Table 8 Relation between the results of US and dual-energy X-ray absorptiometry, Disease Activity Score-28, HAQ score, and radiograph in the patient group

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Table 9 Comparison between the two studied groups regarding the sclerostin

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Table 10 Relation between sclerostin and demographic data of patient group

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Table 11 Correlation between sclerostin, Disease Activity Score-28, HAQ score, and US

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Table 12 Correlation between sclerostin, Hb%, ESR first hour, and ESR second hour

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Table 13 Relation between the results of dual-energy X-ray absorptiometry scan and Disease Activity Score-28, sclerostin, and HAQ score in the patient group

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Table 14 Relation between sclerostin and clinical parameters in the patient group

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Table 15 Relation between the results of US and dual-energy X-ray absorptiometry, sclerostin, Disease Activity Score-28, HAQ score, and radiograph in the patient group

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Statistical analysis

Data shown are the mean±SEM. All statistical analyses for data were performed using SPSS software (SPSS software version 10). Data were analyzed between two groups using Student’s t-test, whereas among more than two groups, data were analyzed by the one-way analysis of variance method. Differences of P value less than 0.05 were considered significant.


  Discussion Top


SOST, the glycoprotein product of the SOST gene, is highly expressed in embedding bone cells such as osteocytes, chondrocytes, and cementocytes [15],[16],[17]. Several Wnt family members seems to be involved in the modulation of the inflammatory response during rheumatoid activity.

The Wnt pathway has been shown to be important for the differentiation of osteoblasts from mesenchymal lineage precursors and endogenous Wnt inhibitors such as DKK-1 and SOST.

SOST might have important roles of osteoclast dysregulation in RA. This protein potently inhibits the Wnt/B-catenin canonical signaling pathway by binding to the low signaling lipoprotein receptor LRP-5/LRP-6, leading to decreased osteo-blastogenesis and osteoblast activity, and thereby, decreasing bone formation [18],[19].

Our results demonstrate that SOST serum levels were significantly increased in the RA group as compared with the control group. Regarding the relation between serum SOST and demographic data of the patients group, there was a statistically significant relation regarding sex (P≤0.05). There was a positive correlation with the age of patients with RA and onset, which might indicate that the older the patients develop RA, the higher the SOST level they have, and this may later on predict a lower bone mass.

In agreement with this study, Francesco et al. [33] found no statistical significant correlation between DAS-28 and HAQ score.

Vis et al. [34] and Szulc et al. [35] found that SOST levels were significantly higher in female patients with RA than in healthy female controls.

In disagreement with this study, Mehaney et al. [22], confirmed by Polyzos et al. [36], did not find a significant difference in serum SOST between patients with RA and the control group.

Gennari et al. [37], confirmed by Amrein et al. [38] and Sheng et al. [39], found that serum SOST level was higher in males than in females. They explained that circulating SOST level might reflect total body skeletal mass. Accordingly, the larger skeleton in men might produce and release more SOST into the circulation [39].

There was a relation of serum SOST level with the disease activity in patients with RA using DAS-28. Vis et al. [34] have found that SOST level is negatively correlated to DAS-28 and correlated serum SOST level to radiological joint damage using van Der Heijde score. Vis et al. [34] found no correlation between van Der Heijde score and SOST levels. However, our results coincide with Vis et al. [34], found a negative correlation with disease activity using DAS-28 , not with whole DAS -28 score but with one of its variables which is the ESR. DKK-1, like SOST, is a national inhibitor of the Wnt signaling [40]. It was studied earlier than SOST in RA and plays a key role in the remodeling of bone and impairs local bone formation, which is particularly deleterious in RA [41].

Wang et al. [42] showed that DKK-1 levels in patients with RA was significantly higher than its levels in healthy controls. It was correlated with the Sharp score of radiological change (r=0.449, P=0.001) in patients with RA.

Gamze et al. [43] found that quantitative measurement of bone loss by DEXA scan may be a useful and practical outcome measure in RA and may be predictive for radiographic progression or functional status in patients with early RA. Human studies have shown a significant increase in serum SOST levels with age [14],[20],[38],[44] and after menopause [20],[44],[45], suggesting that increased serum SOST may be associated with BMD loss induced by aging and menopause [14],[20],[44].

Other studies showed that increased serum SOST concentrations are associated with a greater risk of experiencing fracture in older postmenopausal women [25],[38].

Several reports have demonstrated that RA is highly associated with significant BMD loss mainly in the femoral neck and lumbar spine, where there is greater risk for fracture in these anatomical sites [6],[7],[8],[9].

This study did not determine fracture risk. We did find a significant BMD loss at both vertebral and femoral levels. This finding is in line with several studies demonstrating progressive loss of BMD during evolution of the disease in the right femur and at the vertebral level [9],[12]. Given that patients with RA have a significantly lower BMD than healthy people and that SOST is a potent inhibitor of bone formation, it was initially predicted that serum SOST levels would negatively correlate with BMD in patients with RA.

However, this study results showed a positive correlation between femoral BMD and serum SOST in patients with RA. In partial agreement with our results, it was recently demonstrated that serum SOST levels have a positive correlation with vertebral BMD but not with femoral BMD [28].


  Conclusion Top


This study has some limitations including small sample of patients with RA, most of patients were under treatment with disease-modifying antirheumatic drugs such as methotrexate, fracture risk was not determined in this study, and renal function was not measured.

However, it is possible that circulating SOST levels may not reflect changes of SOST at a local level.

Despite the many questions that remain, preclinical studies and clinical trial results would imply that SOST antibodies will emerge as a dominant first-line treatment in the management of osteoporosis.

Recommendations

Future longitudinal studies will identify whether SOST over-expression aggravates or slows down cardiovascular calcification. Lastly, it will be necessary to determine whether anti-SOST antibodies could slow the progression of vascular calcification or reduce the risk of cardiovascular events.

Future studies are needed to determine SOST levels at a local sites (bone, synovium, and bone marrow) and determine its association with disease progression and bone mineral density in patients with RA.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9], [Table 10], [Table 11], [Table 12], [Table 13], [Table 14], [Table 15]



 

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