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ORIGINAL ARTICLE
Year : 2019  |  Volume : 5  |  Issue : 3  |  Page : 121-127

Prevalence and Risk Factors of Subclinical Vertebral Fractures Among Women with Rheumatoid Arthritis


1 Department of Medicine, Maulana Azad Medical College and Associated Lok Nayak Hospital, Bahadur Shah Zafar Marg, New Delhi, India
2 Department of Radiodiagnosis, Maulana Azad Medical College and Associated Lok Nayak Hospital, Bahadur Shah Zafar Marg, New Delhi, India

Date of Submission15-Jul-2019
Date of Decision09-Nov-2019
Date of Acceptance01-Dec-2019
Date of Web Publication17-Dec-2019

Correspondence Address:
Dr., Associate Professor Sumeet Singla
Room no. 115, First floor, B L Taneja block, Department of Medicine, Maulana Azad Medical College, Bahadur Shah Zafar Marg, New Delhi 110002
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mamcjms.mamcjms_51_19

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  Abstract 


Introduction: Patients of rheumatoid arthritis (RA) are prone to osteoporosis and overt fractures. Subclinical vertebral fractures (SVFs) precede overt vertebral fractures. We studied prevalence and risk factors of SVFs among women with RA. Aim: To determine the prevalence of SVFs in women with RA and to study the various risk factors associated with presence of SVFs. Settings and design: Adult patients of RA attending the rheumatology clinic of medicine department at a tertiary teaching hospital in Delhi. One hundred eleven adult women with RA were included. Clinical assessment included anthropometry, Body Mass Index (BMI), duration of RA, disease activity using Clinical Disease Activity Index (CDAI), disease disability using Health Assessment Questionnaire (HAQ), and details of glucocorticoid (GC) use. Thoracic and lumbar vertebrae were graded for presence of VFs using the semi-quantitative method of Genant by two radiologists. Statistical analysis used: Simple descriptive statistics were used to describe prevalence of SVFs. Risk factors for SVFs were tested for significance using the Studentʼs t-test for quantitative variables and chi-square test for qualitative variables. Kappa statistics were calculated for assessment performed by the two radiologists. Two-sided alpha was set at <0.05. Results: Forty Nine percent women had SVFs; 40% had 1–3 SVFs, and 9% had >3 SVFs. Women with any SVF were significantly older as compared to women with no SVF. Fifty five percent of women using GCs had any SVF, while 44%, not using GC, had any SVF (P = ns). GC use, duration of RA, CDAI score, HAQ score, BMI, presence of RF, and anti-CCP were not different between women with and without SVFs. Kappa for inter-reader variability among the two radiologists was 0.98. Conclusions: This study provides evidence of very high prevalence of SVFs among women with RA. Traditional risk factors do not fully account for this enhanced risk.

Keywords: Rheumatoid arthritis, risk, subclinical, vertebral fractures


How to cite this article:
Singla S, Kumar J, Pandey N. Prevalence and Risk Factors of Subclinical Vertebral Fractures Among Women with Rheumatoid Arthritis. MAMC J Med Sci 2019;5:121-7

How to cite this URL:
Singla S, Kumar J, Pandey N. Prevalence and Risk Factors of Subclinical Vertebral Fractures Among Women with Rheumatoid Arthritis. MAMC J Med Sci [serial online] 2019 [cited 2020 Apr 2];5:121-7. Available from: http://www.mamcjms.in/text.asp?2019/5/3/121/273282

Key Messages: Enhanced vigilance, screening, and bone protection strategies are warranted among women with RA to mitigate risk for future clinical vertebral fractures.





  Introduction Top


Rheumatoid arthritis (RA) is an autoimmune disease characterized by symmetric joint inflammation, stiffness and pain, and muscular weakness around the affected joints. The onset of the disease generally occurs between 40 and 60 years of age.[1] It affects 0.5% to 1% of the general population and has increased prevalence with age.[2],[3]

Vertebral fractures (VFs) are the most common type of fragility fracture. They are associated with chronic back pain, loss of height, kyphosis, reduced pulmonary function, abdominal discomfort, disability, and death. [5],[6] The mortality rate, 5 years after a clinical VF, is 20% greater than expected.[7] Mortality rates increase with the number of VFs. The presence of a VF increases the relative risk of future VFs and fragility fractures at other skeletal sites, independent of bone mineral density (BMD).[8] New VFs, even those that are not recognized clinically (subclinical vertebral fractures, SVF), are associated with substantial increase in back pain and functional limitation.[9] There is also substantial evidence from both cross-sectional and longitudinal studies that radiographically detected SVFs are associated with increased morbidity, functional impairment, and reduced quality of life.[13],[14],[15],[16]

Currently, no Indian study has addressed this important issue. This cross-sectional observational study was planned to document the prevalence of SVFs in Indian women with RA. Presence of SVFs was documented and compared across sub-groups viz. site, disease duration, disease severity, antibody status, age, body weight, BMI, and glucocorticoid (GC) use. By virtue of low socio-economic status, protein malnutrition, low Vitamin D status, low muscle mass, and low body weight Indian women are, per se, susceptible to osteoporosis and fragility fractures. We hypothesize that when the pathological insults due to RA are added to this bone-destructive pathway, the prevalence of fragility fractures (especially SVFs) is likely to be higher than that documented in the Western population. Contribution of various risk factors to SVFs was also determined.

Materials and Methods

The study group comprised of women of RA fulfilling the American College of Rheumatology 2010 criteria for the classification of RA who gave informed consent to participate in the study. [17] Women not willing to give consent, those who were pregnant, diabetic, or those taking bone-protective drugs like bisphosphonates, teriparatide, calcitonin, and raloxifene, were not included in the study. Therapeutic intake of Calcium and Vitamin D was allowed. Women having chronic liver, renal, or thyroid disorders were excluded. Patients having overlap of RA with another connective tissue disorder like systemic lupus erythematosis (SLE), progressive systemic sclerosis (PSS) etc. were not included. A sample size of 100 women was decided, as a sample of convenience. Approval for the study was obtained from the Institutional Ethics Committee. Consecutive patients attending the rheumatology clinic at the Lok Nayak Hospital were screened and their informed consent was taken. After they gave consent, patients were recruited and underwent the following assessments. All patients were asked a detailed history of their disease, treatment, diet, lifestyle, and previous fractures. The disease activity of their RA was judged using the Clinical Disease Activity Index (CDAI) assessment tool.[22] Their quality of life was judged according to the Indian Health Assessment Questionnaire (HAQ).[21] Subsequently, all patients underwent laboratory and radiological tests viz. 5 ml of blood for rheumatoid factor and anti-CCP antibody testing and X-rays of the spine. Two X-rays were done using a standardized procedure after proper bowel preparation: a) lateral X-ray of thoracic spine (T4-T12) and b) lateral X-ray of lumbar spine (L1–L5). Thoracic and lumbar vertebrae were visually graded using the semi-quantitative method of Genant.[18] The films were assessed by two expert radiologists (JK and NP), independently. In case of discordance between the assessment of the two radiologists, the senior radiologist (JK) did a blinded re-assessment of the X-rays and this was taken as the final result. Thoracic and lumbar vertebrae were graded on visual inspection of lateral spinal images and generally without direct vertebral measurement as shown in [Figure 1],[Figure 2] and [Figure 3].
Figure 1 Genant Grade I Vertebral fracture at L1 and L5 levels (black solid arrow)

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Figure 2 Genant Grade 2 vertebral fracture at L3 level (black solid arrow)

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Figure 3 Genant Grade 3 vertebral fractures at L3, L4 and L5 levels (black solid arrows)

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Statistical Analysis

Data recorded in the case forms were collated and analyzed. Results were expressed as means. SVF prevalence was calculated for site, disease duration and compared between two sub-groups, that is, those having no GC exposure and those having had any GC use. Risk factors for SVFs were tested for significance using the Student’s t-test for quantitative variables and chi-square test for qualitative variables. Univariate statistical analyses were performed by categorizing patients into three groups based on the result of the semi-quantitative vertebral deformity analysis—no vertebral deformity, any vertebral deformity, or multiple vertebral deformities. Multivariate regression analysis was used to estimate the independent effects of some clinical and laboratory variables for the presence of VFs. Level of inter-observer concordance (kappa) was calculated for the assessment performed by the two radiologists. The level of significance was set at P < 0.05. All tests were two-sided. Statistical analysis was performed with the SPSS program (version 21.0, SPSS Inc., Chicago, III).


  Results Top


We recruited 111 women with RA in the study. The baseline demographic variables of these women are shown in [Table 1].
Table 1 Baseline demographics of the study group of women with RA

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Forty nine percent of the studied women with RA had any SVF; 9% had more than 3 SVFs. The total number of SVFs were 116. The average number of SVFs per woman were 2.15 (range 1–10).

Disease duration and disease activity (as measured by CDAI) are shown in the box-whiskers plots in [Figure 4] and [Figure 5]. Neither were significantly different among women with and without SVFs. The distribution of autoantibody (RF and ACPA) positivity among women with and without SVFs is shown in [Figure 6] and [Figure 7]. There was no significant difference in the distribution of women who were seropositive or seronegative for either antibodies, with respect to the presence of SVFs.
Figure 4 Comparison of disease duration among women with and without SVF

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Figure 5 Comparison of CDAI scores among women with and without SVF

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Figure 6 Proportion of Seropositive (RF+) and Seronegative (RF-) women

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Figure 7 Proportion of Seropositive (ACPA+) and Seronegative (ACPA-) women

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ANOVA testing revealed that the variable which was significantly different among women with SVF and those without SVF was age. Women with no SVF were significantly younger than women with >3 SVF. Also, women with 1–3 SVF were significantly younger than women with >3 SVF.

Among the risk factors studied for SVF, 41 women used GC; average cumulative GC dose was 1150 mg. 55% of women using GCs had any SVF, while 44% women not using GC, had any SVF [Figure 8]. The difference of SVF among these two groups of GC use was not statistically significant.
Figure 8 Comparison of Glucocorticoid use among women with and without SVF

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Kappa for inter-reader reliability of the radiographic readings among the two radiologists was 0.98 suggesting a high degree of agreement and thus, accuracy of the Genant scoring.

In summary, our results show that women with any SVF were significantly older as compared to women with no SVF. Duration of RA, CDAI score, HAQ score, BMI, presence of RF, and anti-CCP and GC use were not different between women with and without SVFs.


  Discussion Top


The prevalence of SVF was quite high in our study, at 49%. This is higher than the prevalence of clinical VFs as reported by Magharoui et al.[10] But they had studied clinically overt VFs while we have studied subclinical VFs, which, like all, clinical diseases have a subclinical phase and all do not convert to clinical fractures.

Osteoporosis and fragility fractures are well-known complications of RA.[4] The cause of osteoporosis in RA may be enhanced osteoclastic activity due to inflammatory cytokines and physical inactivity. Studies have demonstrated higher prevalence of VFs in patients with RA than controls, ranging from 22% to 36%.[10],[11] Several studies have also shown that the risk of vertebral or hip fractures is higher in patients with RA than in those with primary (postmenopausal) osteoporosis.[12],[13] This risk has been estimated to be more than two times than in non-RA women. Furthermore, evidence from studies with BMD as the primary endpoint suggests that osteoporosis occurs in patients with RA independently of GC use.[14],[15] However, there is a discrepancy between low BMD and fracture risk, and a number of fractures are observed in RA patients with T-scores, which are not in the osteoporotic range.[16],[17] This discrepancy may be related to alterations of bone quality, which are not captured by BMD measurements such as mineralization, bone matrix, microarchitecture and have been ascribed to inflammation and GC use.

The spine is a key fracture site; however, there is strong evidence of widespread under-diagnosis of VFs. It has been estimated that only 30% of VFs receive clinical attention (which means that the majority of patients with VFs remain undetected).[18] Large-scale prospective studies indicate that only about one in four VFs are clinically recognized.[19] The lack of clinical recognition of fractures (SVFs) is due to both the absence of symptoms and difficulty in determining the cause of symptoms. VFs are not commonly suspected in patients reporting back pain, unless associated with trauma. Because it is often unsuspected clinically, the diagnosis of a VF relies heavily on radiography. Yet, in a study, 50% of radiographic reports failed to report the presence of moderate or severe VFs and many patients (>90%) remained untreated.[20]

In our study, as the age of the patients increased, the number of SVF increased. The lack of association of SVF with risk factors like duration of RA, CDAI score, HAQ score, BMI, presence of RF, and anti-CCP antibodies could be due to small sample size.

Surprisingly, GC use did not confer a higher risk for SVFs in the study as was reported by earlier studies.[14],[15] This may be because of the low cumulative dose of GC (1150 mg) used by patients in our study.

As many VFs are clinically unappreciated and undiagnosed, but convey increased risk for future fracture and quality of life impairment, knowledge of existing fracture status is necessary for the optimal management. Moreover, the diagnosis and treatment of VFs are attempted only when the patient becomes significantly symptomatic or in asymptomatic patients by using expensive techniques such as BMD assessment by DEXA scanning. The most glaring lacuna is the clinico-radiologic under-appreciation of the importance of SVFs and the need to search for them actively, so that an early, comprehensive bone-protection strategy can be initiated in concordance with appropriate anti-inflammatory therapy in patients with RA.

A simple, cheap, relatively harmless, widely available, and (till date) most standardized radiographic tool like X-ray was used in our study. Recently, it has been shown that the inter-reader reproducibility of the semi-quantitative approach, in the hands of experienced and trained readers, has a high degree of reliability for the identification of vertebral deformities.[23]

Our study has some lacunae. The sample size was small and we did not have enough patients so that some associations with conventional risk factors for osteoporosis and VFs may have been missed. We did not recruit healthy controls to check and compare the prevalence of SVFs in the normal population, due to denial of permission from the ethics committee.

We did not check serum levels of Vitamin D, calcium, and DEXA bone densitometry to objectively assess bone density. Further, since this was a point prevalence study, we do not have longitudinal data of women who had subclinical VFs.

The key message from our study is that almost half of the women with RA have more than two subclinical VFs, on an average. They portend a higher risk of overt fractures in the future. These covert fractures could not be accounted for by traditional risk factors and hence, all physicians caring for these women should be aware. Bone-protection and bone-strengthening measures must be reinforced at each visit.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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AIHW: Snapshot of arthritis in Australia 2010. Canberra: Australian Institute of Health and Welfare; 2010.  Back to cited text no. 1
    
2.
Lawrence RC, Helmick CG, Arnett FC et al. Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States. Arthritis Rheum 1998;41:778-99.  Back to cited text no. 2
    
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Kvien TK, Glennas A, Knudsrod OG, Smedstad LM, Mowinckel P, Forre O. The prevalence and severity of rheumatoid arthritis in Oslo: results from a county register and a population survey. Scand J Rheumatol 1997;26:412-8.  Back to cited text no. 3
    
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Kvien TK, Haugeberg G, Uhlig T et al. Data driven attempt to create a clinical algorithm for identification of women with rheumatoid arthritis at high risk of osteoporosis. Ann Rheum Dis 2000;59:805-11.  Back to cited text no. 4
    
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Jalava T, Sarna S, Pylkkanen L et al. Association between vertebral fracture and increased mortality in osteoporotic patients. J Bone Miner Res 2003;18:1254-60.  Back to cited text no. 5
    
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Naves M, Diaz-Lopez JB, Gomez C et al. The effect of vertebral fracture as a risk factor for osteoporotic fracture and mortality in a Spanish population. Osteoporosis Int 2003;14:520-4.  Back to cited text no. 6
    
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Pongchaiyakul C, Nguyen ND, Jones G, Center JR, Eisman JA, Nguyen TV. Asymptomatic vertebral deformity as a major risk factor for subsequent fractures and mortality: a long-term prospective study. J Bone Miner Res 2005;20:1349-55.  Back to cited text no. 7
    
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Lindsay R, Silverman SL, Cooper C et al. Risk of new vertebral fracture in the year following a fracture. JAMA 2001;285:320-3.  Back to cited text no. 8
    
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Jacobs-Kosmin D, Sandorfi N, Murray H, Abruzzo JL. Vertebral deformities identified by vertebral fracture assessment: associations with clinical characteristics and bone mineral density. J Clin Densitom 2005;8:267-72.  Back to cited text no. 9
    
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Maghraoui AE, Rezqi A, Mounach A, Achemlal L, Bezza A, Ghozlani I. Prevalence and risk factors of vertebral fractures in women with rheumatoid arthritis using vertebral fracture assessment. Rheumatology 2010;49:1303-10.  Back to cited text no. 10
    
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Lentle BC, Brown JP, Khan A et al. Recognising and reporting vertebral fractures: reducing the risk of future osteoporotic fractures. Can Assoc Radiol J 2007;58:27-36.  Back to cited text no. 11
    
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Ettinger B, Black DM, Nevitt MC et al. Study of Osteoporotic Fractures Research Group.Contribution of vertebral deformities to chronic back pain and disability. J Bone Miner Res 1992;7:449-56.  Back to cited text no. 13
    
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Nevitt MC, Ettinger B, Black DM et al. The association of radiographically detected vertebral fractures with back pain and function: a prospective study. Ann Intern Med 1998;128:793-800.  Back to cited text no. 14
    
15.
Hall SE, Criddle RA, Comito TL, Prince RL. A case-control study of quality of life and functional impairment in women with long-standing vertebral osteoporotic fracture. Osteoporosis Int. 1999;9:508-15.  Back to cited text no. 15
    
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Matthis C, Weber U, O’Neill TW, Raspe H. Health impact associated with vertebral deformities: results from the European Vertebral Osteoporosis Study (EVOS). Osteoporosis Int 1998;8:364-72.  Back to cited text no. 16
    
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Arnett FC, Edworthy SM, Bloch DA et al. The American Rheumatism Association 2010 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 2010;31:315e324.  Back to cited text no. 17
    
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Genant HK, Wu CY, van Kujik C, Nevitt MC. Vertebral fracture assessment using a semiquantitative technique. J Bone Miner Res 1993;8(9):1137-48.  Back to cited text no. 18
    
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Wu CY, Li J, Jergas M, Genant HK. Comparison of semiquantitative and quantitative techniques for the assessment of prevalent and incident vertebral fractures. Osteoporosis Int 1995;5:354-70.  Back to cited text no. 19
    
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Van Brussel MS, Lems WF. Clinical relevance of diagnosing vertebral fractures by vertebral fracture assessment. Curr Osteoporos Rep 2009;7:1036.  Back to cited text no. 20
    
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Kumar R, Malaviya AN, Pandhi A, Singh R. Validation of an Indian version of the Health Assessment Questionnaire in patients with rheumatoid arthritis. Rheumatol 2002;41:1457-9.  Back to cited text no. 21
    
22.
Aletaha D, Smolen J. The Simplified Disease Activity Index (SDAI) and the Clinical Disease Activity Index (CDAI): a review of their usefulness and validity in rheumatoid arthritis. Rheumatol 2005;23:S100-8.  Back to cited text no. 22
    
23.
Grigor C, Capell H, Stirling A et al. Effect of a treatment strategy of tight control for rheumatoid arthritis: a single-blind randomized controlled trial. Lancet 2004;364:263-9.  Back to cited text no. 23
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]
 
 
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