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ORIGINAL ARTICLE Table of Contents  
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Association of hypovitaminosis D with poor bone health in patients of rheumatoid arthritis – A case–control study


1 Department of Medicine, Army Hospital (Research and Referral), Delhi, India
2 Department of Medicine, Armed Forces Medical College, Pune, Maharashtra, India

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Date of Submission30-Jun-2022
Date of Decision26-Jul-2022
Date of Acceptance16-Aug-2022
Date of Web Publication07-Oct-2022
 

  Abstract 


Background: Data on correlation between hypovitaminosis D and disease activity indices in patients with rheumatoid arthritis (RA) are varied. In this context, this prospective, case–control study aimed to evaluate the contribution of hypovitaminosis D toward bone health in patients with RA and correlate it with clinical, functional, and radiological disease activity indices. The study objectives were to assess the occurrence of hypovitaminosis D, to determine baseline bone mineral density (BMD), and to evaluate factors likely to contribute to poor bone health in patients of RA. Results: Hypovitaminosis D was observed in 76% of patients of RA with all of them having poor bone health as evident by statistically significant correlation between low Vitamin D levels and poor BMD. Poor bone health was observed in 80% of patients with femoral measurements, exhibiting greater severity of reduced BMD than lumbar spine values. Bivariate analysis revealed significant correlation of low Vitamin D, parathyroid hormone, Modified Sharp Score (MSS), and steroid intake with poor BMD at both spine and femur neck. Furthermore, binary logistic regression analysis among these four variables showed that only MSS had statistically significant association with osteoporosis, and there was a trend towards significance with poor BMD. Conclusions: This study has observed that RA patients indeed have poor bone health. Consequent osteoporosis has multifactorial etiology, and hypovitaminosis D remains one of the prime contributors, yet underappreciated and consequently undertreated.

Keywords: Hypovitaminosis D, Modified Sharp Score, Osteoporosis, Rheumatoid Arthritis


How to cite this URL:
Sood V, Sharma M, Chauhan P, Dogra P M, Kumar A, Subramanian S. Association of hypovitaminosis D with poor bone health in patients of rheumatoid arthritis – A case–control study. APIK J Int Med [Epub ahead of print] [cited 2022 Dec 4]. Available from: https://www.ajim.in/preprintarticle.asp?id=358059





  Introduction Top


Rheumatoid arthritis (RA) is a chronic inflammatory symmetric polyarthritis characterized by synovitis of the peripheral joints, with several extra-articular manifestations, leading to severe disability and premature mortality.[1] The worldwide prevalence of RA is 0.8% of the population[2] (range 0.3%–2.1%); women are affected approximately three times more often than men. American College of Rheumatology/European League Against Rheumatism (ACR/EULAR)-2010 classification criteria[3] redefined the current paradigm of RA by focusing on features at earlier stages of disease, rather than defining the disease by its late-stage features.

Bone involvement in RA may result in erosions, periarticular osteopenia, and generalized osteoporosis involving the axial and appendicular skeleton.[4] Consequent poor bone health is a matter of significant concern in patients of RA, with a prevalence close to 75%.[5] Etiology of poor bone health in patients of RA is multifactorial[6] and includes female sex (particularly postmenopausal), reduced physical activity, hypovitaminosis D, avoidance of sunlight exposure, abnormalities of Vitamin D hydroxylation consequent to renal involvement, premature gonadal failure due to the disease itself or secondary to cytotoxic therapy, cytokine-mediated stimulation of bone resorption and suppression of osteogenesis, and occasionally early-onset RA secondary to inability to attain optimal peak bone mass at skeletal maturity.

Vitamin D is believed to have immunomodulatory and anti-inflammatory activities.[7] Its deficiency correlates with disease severity in patients with RA.[8] A recent meta-analysis[9] of over thousand RA patients also showed a significant inverse correlation between Vitamin D levels and Disease Activity Score (DAS-28); however, correlation with radiological indices such as Modified Sharp Score (MSS) is infrequently reported. In this context, the present study aimed to evaluate the contribution of hypovitaminosis D towards bone health of Indian patients with RA and correlate it with clinical, functional, and radiological disease activity indices.


  Methods Top


Study design

The study was a prospective, case–control study, conducted in the Department of Medicine, Armed Forces Medical College (AFMC), Pune, India. All consecutive patients of RA (satisfying the ACR/EULAR classification criteria) attending the rheumatology clinic over a period of 6 months were screened for eligibility. Inclusion criteria were patients aged between 18 and 55 years and with disease duration of at least 2 years. Exclusion criteria were patients with spondyloarthropathy/reactive arthritis/other connective tissue disorders, patients with past or present diagnosis of malignancy/chronic liver or kidney disease/diabetes mellitus, diseases associated with hypercalcaemia (hyperparathyroidism/hyperthyroidism/sarcoidosis/tuberculosis), patients on Vitamin D supplementation in the past 6 months or on medications that can affect bone and Vitamin D metabolism (anticonvulsants, diuretics, and thyroxin), pregnant or lactating females, and patients with life expectancy <1 year. A total of 50 patients of RA and an equal age and sex-matched asymptomatic cohort (relatives/healthy volunteers) were included as controls. All patients provided written informed consent before enrolment.

Objectives

The primary objective was to assess the occurrence of hypovitaminosis D in patients of RA. The secondary objectives were to determine the baseline bone mineral density (BMD) in patients of RA and to evaluate various factors likely to contribute to poor bone health.

Historical assessment

At enrolment, detailed history was taken from patients regarding age at onset of symptoms, disease duration, pattern of joint involvement, presence of swelling and pain in the joints, and drug history including disease-modifying antirheumatic drug (DMARD)-naïve period (<1 year or >1 year) and steroid intake (prolonged, intermittent, and steroid naive).

Prolonged intake was defined as intake >10 mg/day of prednisolone or equivalent for a period of 6 months; an intake lesser than this was considered to be intermediate.

Clinical assessment

Musculoskeletal examination included evaluation for tenderness, swelling, and restriction of movements of affected joints. Disease activity[10] was ascertained by tender joint count, swollen joint count, patient global assessment (PGA), and physician's global assessment (PhGA). Both PGA and PhGA were scaled between 0 and 10, where 10 signified maximal disease activity. Functional assessment[11] included Simplified Disease Activity Index (SDAI), Clinical Disease Activity Index (CDAI), DAS-28,[12] and Indian Health Assessment Questionnaire. RA was considered in remission[13] for scores ≤3.3 SDAI or ≤2.8 CDAI or ≤2.4 DAS-28. Low disease activity was considered for scores ≤11 SDAI or ≤10 CDAI or ≤3.6 DAS-28. Disease activity was considered moderate for scores ≤26 SDAI or ≤22 CDAI or ≤5.5 DAS-28 and high for scores beyond respective limits.

Laboratory assessment

Tests constituted hematological and biochemical profile including calcium, phosphorus, and alkaline phosphatase. Specific investigations included erythrocyte sedimentation rate (ESR), rheumatoid factor, anticyclic citrullinated peptide (anti-CCP), Vitamin D, and intact parathyroid hormone (iPTH). Vitamin D levels >30 ng/ml were considered as normal, between 11 and 30 ng/mL as insufficient, and <10 ng/mL as deficiency.[14]

Radiological assessment

Tests constituted radiographs of both hands (posteroanterior view) and subsequent scoring for joint damage using MSS,[15] wherein 17 joints of hands were assessed to evaluate erosion score (range 0–5/joint, maximum score 170) and 18 joints for joint space narrowing (range 0–4/joint, maximum score 144). The cumulative score was the addition of these two components (maximum score 314). All radiographs were scored by two observers till the concordance achieved was >90%. They were scored again a fortnight later to determine intraobserver variation (concordance noted >0.90). Dual-energy X-ray absorptiometry (DEXA) scan of the lumbar spine (LS) (L1–L4) and femur neck (FN) (using Lunar Prodigy Advance System; General Electronics) was used for the assessment of BMD. Patients were categorized by the lowest T score of LS or FN and objectively classified into normal/osteopenia/osteoporosis.[16]

Statistical analysis

Assuming dropout rate of 20%, the sample size of at least 100 subjects (50 in either group) was required to detect absolute difference (standard deviation [SD] ±5%) between the two groups with 80% power and two-sided α of 0.05. All enrolled patients with nonmissing outcome data were included for analysis. Descriptive statistics were used to describe the characteristics of the study subjects. Data have been presented as mean ± SD (95% confidence interval) and median (interquartile range) as appropriate. Continuous variables were compared with independent samples paired t-test if normally distributed or Mann–Whitney U-test if the distribution was skewed. Categorical variables were analyzed with Chi-square test or Fisher's exact test as appropriate. Normality of data was checked using graphics (histograms, Box and Whisker plots, and Q-Q plots) and statistically by measures of skewness and kurtosis and Kolmogorov–Smirnov tests of normality. Pearson's correlation coefficient was calculated to find the correlation between BMD and different quantitative variables. Paired t-test and Wilcoxon signed-rank test were used for within-group comparisons. Factors possibly influencing BMD in patients with RA were tested for correlation using logistic regression analysis. Two-tailed P < 0.05 was considered statistically significant. Analyses were conducted using SPSS software for Macintosh version 21.0 (IBM SPSS, Chicago, IL, USA).

Ethical considerations

The study did not entail any additional risk over and above of what was conferred by subject's underlying disease status. Participation in this study was absolutely voluntary. The study was approved by the institute's ethics committee. Patients who refused to participate were continued treatment at our center without any bias or discrimination. All data were stored pseudonymously in a confidential manner.


  Results Top


A total of 147 patients with RA were screened and assessed for eligibility. Overall, 50 patients (female 41, male 9) satisfying both inclusion and exclusion criteria were enrolled [Figure 1]. Fifty asymptomatic age and sex-matched asymptomatic volunteers (mostly relatives) were included as control group.
Figure 1: Trial consort

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Clinical profile

The mean (SD) age was 44.32 ± 10.64 years and the mean disease duration was 9.08 ± 3.78 years. Among female patients (n = 41/50), the mean body mass index was 25.46 ± 3.8 kg/m2, and 17% of patients (n = 7/41) were postmenopausal. Sixty-four percent patients (n = 32/50) had disease duration beyond 7 years. Seropositivity for rheumatoid factor was observed in 72% of patients (n = 36/50) and for anti-CCP in 28% of patients (n = 14/50). Mean DMARD-naïve period observed was 2.02 ± 1.40 years (minimum - 6 months and maximum - 18 years). Disease activity indices revealed high activity scores suggesting moderate-to-severe disease activity in majority [Table 1]. Hypocalcemia was observed in 60% of patients (n = 30/50); however, calcium phosphorus product was normal in majority (88%; n = 44/50). Twelve percent of patients (n = 6/50) with laboratory evidence of secondary hyperparathyroidism (SHPT) had calcium phosphorus product approaching 55. Reduction in BMD at either the LS or FN was observed in 82% of patients (osteopenia [60%; n = 30/50]/osteoporosis [22%; n = 11/50]) reflecting poor bone health as against osteopenia in 20% (n = 10/50) of age and sex-matched asymptomatic cohort. FN measurements exhibited greater severity of reduced BMD than LS values [Table 2]. Likewise, hypovitaminosis D observed in 76% of patients (deficiency - 32%; n = 16/50 and insufficiency - 44%; n = 22/50) was statistically significant [Table 3] when compared to control cohort (deficiency - 8%; n = 4/50 and insufficiency - 36%; n = 18/50).
Table 1: Disease activity indices

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Table 2: Mineral bone profile and bone mineral density in cases and control

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Table 3: Vitamin D levels in cases and control

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Analysis of factors resulting in osteoporosis

Patients detected to have osteoporosis (22%; n = 11/50) on the basis of T score (FN/LS) were analyzed against presumable implicating factors [Table 4] for possible correlation. There was statistically significant association of Vitamin D, iPTH, MSS, and steroid intake with osteoporosis. However, association with respect to duration of illness, DMARD-naïve period, Health Assessment Questionnaire (HAQ), DAS-28, CDAI, and ESR was not statistically significant.
Table 4: Analysis of factors resulting in osteoporosis

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Analysis of factors resulting in poor bone mineral density (osteopenia/osteoporosis)

Patients with poor bone health (82%; n = 41/50) including patients detected to have osteopenia (60%; n = 30/50) were analyzed against presumable implicating factors [Table 5] for possible correlation. Even then, Vitamin D, iPTH, MSS, and steroid intake showed statistically significant correlation with poor BMD, and association with respect to duration of illness, DMARD-naïve period, HAQ, DAS-28, CDAI, and ESR was not statistically significant.
Table 5: Analysis of factors resulting in poor bone mineral density (osteopenia/osteoporosis)

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Correlation between bone mineral density (lumbar spine and femur neck) with factors contributing to poor bone health

Vitamin D, iPTH, and MSS had statistically significant correlation with BMD both at LS as well as FN; however, correlation with HAQ, DAS-28, CDAI and ESR was not significant at LS as well as FN [Table 6].
Table 6: Correlation between bone mineral density and factors likely contributing to poor bone health

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Binary logistic regression analysis of factors resulting in osteoporosis and poor bone mineral density

Analysis using binary logistic regression method [Table 7] between four variables (Vitamin D, iPTH, MSS, and steroid intake) showed that only MSS had statistically significant association with osteoporosis (P = 0.023), and there was a trend toward significance for patients with poor BMD (P = 0.058). Odds ratio of MSS, Vitamin D, and iPTH was significant with respect to both osteoporosis and Vitamin D and steroid intake with respect to poor BMD. Wald test also showed significant relation of MSS and Vitamin D with poor BMD.
Table 7: Binary logistic regression analysis of factors resulting in osteoporosis/poor bone mineral density

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  Discussion Top


This study aimed to look at the contribution of hypovitaminosis D towards poor bone health in patients of RA. It was observed that 76% of patients had hypovitaminosis D (Vitamin D insufficiency/deficiency), and most of them had poor (osteopenia/osteoporosis) bone health. Statistically also, there was significant correlation between low Vitamin D levels and poor BMD. Although all patients had normal calcium phosphorus product (<55), 12% of patients had biochemical evidence of SHPT.

This study has also shown a reduction of BMD in the LS or FN in about 80% of patients contributing to poor bone health (osteopenia or osteoporosis). FN measurements exhibited greater severity of reduced BMD than LS values. It is well known that trabecular bone loss is more prominent than cortical bone loss in osteoporosis. Therefore, it is expected that BMD might be lower in the lumbar region which is rich of trabecular bone when compared to the femoral area. Lower BMD values for femoral region as evident in the index study could possibly be attributed to new bone formation in the LS (syndesmophytes, interapophyseal joint, and interpedicular ankylosis) rather than differences in bone remodeling between these two sites.

Initial assessment had revealed that factors related with low BMD were similar at LS and FN. Using bivariate analysis, factors relating to low BMD were hypovitaminosis D, iPTH, MSS, and steroid intake. Binary logistic regression analysis, amongst these four variables, revealed that only MSS had statistically significant association with osteoporosis, and there was a trend towards significance for patients with poor BMD.

MSS is a validated radiological score that reflects cumulative radiographic damage over time. The observed association between radiological joint lesions and low BMD in index study may suggest an interrelation between cumulative disease damage and consequent poor bone health. Despite statistical significance in BMD and Vitamin D levels between enrolled patients and age and sex-matched cohort, postmenopausal status in 17% of the enrolled cohort could have possibly attributed further to low BMD,[5] besides physical inactivity which also contributes to progressive joint damage with subsequent decrease in muscle strength, and consequent less loading of the bone.[17]

Corticosteroids are a well-known risk factor for osteoporosis.[18] Prolonged steroid intake[19] (for at least 6 months) has significant association with osteoporosis as well as poor BMD as evident in our study. However, after using binary logistic regression analysis, association of steroid intake with poor BMD was not statistically significant. This can presumably be explained by a smaller number of prolonged steroid users and the arbitrary classification employed (prolonged use/intermediate use/steroid naïve), which might not have been discriminatory enough to detect mild differences. It is plausible to have different results in a longitudinal study with accurate records of corticosteroid intake.

The study did not find significant correlation between poor bone health and factors such as duration of illness and DMARD-naïve period presumably due to the fact that bone loss is a continuous process and must have been initiated within the first few years itself. Hence, a longer disease duration/DMARD-naïve period might have failed to show any further association. Likewise, correlation between poor bone health and composite disease activity indices (DAS-28, CDAI, and SDAI) was also not significant possibly consequent to moderate-to-severe disease activity as evident by high activity scores in most of the enrolled patients.

Limitations

The study had inherent limitations of being a cross-sectional, single-center study, with a small cohort. As poor bone health in patients of RA has multifaceted etiology, we addressed mainly on factors related to RA (disease duration, disease activity, DMARD-naïve period, duration of steroid intake, and hypovitaminosis D). Nevertheless, contribution of factors including physical activity, nutritional status, postmenopausal status, and sunlight exposure, remains undeniable and might have been trivialized in the index study.


  Conclusions Top


The study has reemphasized poor bone health in patients of RA, etiology of which is probably multifactorial with hypovitaminosis D being one of the prime contributors, yet underappreciated and consequently undertreated.

Acknowledgments

We would like to acknowledge Departments of Rheumatology, Endocrinology and Radiology, AFMC, Pune.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Correspondence Address:
Vivek Sood,
Department of Nephrology, Army Hospital (Research and Referral), New Delhi - 110 010
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ajim.ajim_89_22



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