Rheumatoid arthritis (RA), a systemic autoimmune disorder that primarily affects the synovial tissues, is one of the most debilitating types of arthritis affecting approximately 1–2% of the world population. RA causes inflammation, pain, stiffness, swelling, and disability of the joint, thus limiting mobility in the affected joints and curtailing individuals with RA the ability to perform basic daily tasks. The onset of RA is typical during middle age, although reports have also suggested the development of RA at a younger age, and the incidences of RA are 2 to 3 times more common in women than in men[2,3].
Patients with RA are at risk of osteoporosis and osteoporotic fractures.[4–6] Clinical studies have shown that the incidence of osteoporosis among RA patients is 1.9 times higher than among non-RA patients. Bone loss in RA has been associated with many factors including chronic inflammation, use of glucocorticoids, and physical inactivity. The release of pro-inflammatory cytokines such as interleukin-1 (IL-1), IL-6, and tumor necrosis factor-α (TNF-α) may cause the abnormal production of osteoclasts, thus disrupting the equilibrium between bone resorption and bone formation.[8–10] Secretion of receptor activator of nuclear factor kappa B ligand (RANKL) by activated T lymphocytes has also been observed to induce the differentiation of synovial macrophages into osteoclasts, leading to bone loss.[11,12] Oral glucocorticoids, clinical drugs commonly used to suppress RA-induced inflammation, can ironically promote the loss of bone mass by inhibiting the differentiation and activity of osteoblasts through the blockage of bone morphogenetic protein 2 (BMP-2)  or the Wnt/beta-catenine pathways.[14,15] Meanwhile, immobility resulting from RA-induced muscle pain, weakness, and swelling may increase the risk of falling by a certain extent,[16,17] thereby raising the rate of bone fracture. The mortality rate from osteoporotic fractures is higher than any other mortality including cervical cancer, uterine cancer, or breast cancer. Therefore, the study of osteoporosis and osteoporotic fracture in RA patients is important for the early intervention and prevention of bone fracture.
Over the years, numerous observational studies have associated patients with RA with the increased risk of osteoporosis fracture involving mainly the hip or vertebral.[19–21] However, most clinical studies performed are either limited in sample size, restricted to certain subpopulation, or are fracture-site specific. The risk of bone fracture in RA patients has not been summarized and little is known whether the risk of fracture is site-specific. To the best of our knowledge, no meta-analysis has been performed to conclude the assessment of bone fracture risk in RA patients. Therefore, the present study aims to evaluate the overall risk of bone fracture associated with RA.
2 Materials and methods
This study was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. As a meta-analysis study based on previous studies, ethical approval and informed consent were, therefore, not required.
3 Inclusion criteria
Subjects were eligible for inclusion if they were diagnosed with RA based on the diagnostic criteria published by the American Rheumatism Association (ARA) or the American College of Rheumatology 1987 (ACR). Eligibility of subjects was not restricted by race and sex. Subjects without RA and any other conditions that are known to affect bone mass are defined as the control group.
3.2 Studies outcomes
The primary outcome of interest is the incidence of bone fracture. The secondary outcome of interest is the incidence of hip fracture or vertebral fracture (also known as the spine fracture).
3.3 Types of studies
Only retrospective or prospective studies published in English or Chinese were included.
3.4 Exclusion criteria
The exclusion criteria were as follows:
- Studies on subjects without clearly defined diagnosis, and inclusion and exclusion criteria.
- Studies that reported the rate of mortality as outcome, that is, standard mortality rate (SMR).
- Studies with inaccurate or incomplete data and were unable to provide outcome.
- Studies published repeatedly.
3.5 Search strategy
We conducted a systematic search in PubMed, EMBASE, and OVID databases using the MeSH terms and free key words “rheumatoid arthritis” combined with “Fracture,” to identify relevant studies published from inception through April 1, 2016. Language restrictions were not employed. We also searched the reference lists for full-text papers and all relevant publications were reviewed to identify any omitted studies.
3.6 Literature selection
Literatures were imported into EndNote software to check for completeness of volume, issue, and abstract. Important information was copied and edited; and, the literatures that met the criteria were retained. For the manuscripts that did not fulfill inclusion criteria, the original documents were read to determine eligibility; literatures were marked with “include,” “pending,” or “exclude” (with reasons). For articles marked with “pending,” full-text articles were retrieved from references and further reviewed to determine eligibility.
3.7 Quality assessment
The Newcastle-Ottawa Scale (NOS) was used to evaluate the quality of the studies included. Specifically, the studies were evaluated on 8 items, categorized into 3 aspects: the selection of the study groups, the comparability of the groups, and the ascertainment of the outcome of interest. NOS employed the star system to provide a semi-quantitative appraisal for the overall quality of each cohort study. The highest quality studies were awarded up to 9 stars.
3.8 Data extraction
A self-designed data abstraction form was used to record the following information: first author and publication year, type of study, country where the study was conducted, inclusion criteria of participants, cases of RA, incidences of fractures in RA and non-RA participants, outcome measurement, confounders adjusted for, and matching baseline factors.
Data selection, evaluation, and extraction were performed by 2 independent investigators. Discrepancies were solved by discussion to consensus or by the assistance of a third investigator.
3.9 Outcome measurement
The primary outcome of interest for our study is the indicators associated with RA and bone fracture, which is calculated in risk ratio (RR), odds ratio (OR), and hazard ratio (HR) with 95% confidence interval (CI).
3.10 Statistical analysis
Statistical analysis was conducted using Stata13.1 software. All ratios (risk ratio (RR), odds ratio (OR), and hazard ratio (HR)) were combined to obtain an accurate and comprehensive statistical analysis. Pooled RR and its 95% confidence interval (CI) were calculated. A chi-squared test (χ2) was used to test the included studies for statistical evidence of heterogeneity, and the degree of heterogeneity among studies was assessed with I2 statistic. When no significant heterogeneity was observed (P > .1, I2 ≤ 50%), data were analyzed using the fixed-effects model. When heterogeneity was observed (P ≤ .1, I2 > 50%), the studies were analyzed with the random-effects model. The sources of heterogeneity were evaluated by subgroup analyses (i.e., sex and site-specific fractures).
A sensitivity analysis was performed to assess the robustness of the overall effect size. The included studies were omitted one at a time and the pooled RRs were recalculated to determine if there was any change to the overall estimates.
Publication bias was assessed using the funnel plot. An asymmetry in the plot was further evaluated using Egger's test. P < .05 was considered to be significantly bias.
4.1.1 Study selection
A total of 2956 articles were identified using the systematic literature search; 227 duplicates were removed, and 2659 articles did not meet the selection criteria. The remaining 70 full-text articles were retrieved for detailed evaluation. In total, 57 articles were excluded for the following reasons: did not fulfill selection criteria (n = 14), did not meet intervention method (n = 9), control group did not meet intervention method (n = 16), and ambiguous outcome (n = 18). Thus, 13 articles met the inclusion criteria for this meta-analysis (Fig. 1).[4,19–21,26–34]
4.2 Quality assessment
Individual studies were scored on the Newcastle-Ottawa Scale (NOS); 9 studies scored 8 out of 9,[4,19,21,26,27,30,31,33,34] 2 studies scored 7 out of 9,[28,32] and 2 studies scored 6 out of 9[20,29] (Table 1). Overall, the 13 included studies were considered as high-quality studies.
4.3 Characteristics of included studies
A total of 13 studies that reported RR, OR, or HR were included in the meta-analysis to assess the association between RA and bone fracture. The studies were conducted in countries including the United States, United Kingdom, Sweden, Norway, Finland, Australia, and China. Various matching factors were considered when selecting controls, including age, sex, age or years of menopause, height, weight, body mass index (BMI), residential area, and smoking habits. Six studies[4,20,21,28–30] performed adjusted risks of fractures in RA patients to reduce potential confounders involving age, sex, BMI, smoking habits, previous history of fracture or fall, joint or hormone replacement therapy, and calcium, vitamin D, or other medication intake. The characteristics of each study are listed in Table 2.
4.4 Association of RA with bone fracture risk
The risk of a bone fracture was compared between the RA and non-RA patients. Meta-analysis showed strong heterogeneity (P < .0001, I2 = 96.5%) among the studies; thus, a random-effects model was employed to analyze the data. Our results show that patients with RA have a significantly higher risk of bone fracture compared to patients without RA (RR = 2.25, 95% CI [1.76–2.87]) (Fig. 2).
Studies have also suggested that RA affects more women than men. Therefore, we also performed subgroup analysis based on sex. Our results showed that the risks of bone fracture are significantly higher in both women and men with RA than in women and men without RA (women: RR = 1.99, 95% CI [1.58–2.50]; men: RR = 1.87, 95% CI [1.48–2.37]) (Fig. 3A).
Subgroup analyses of site-specific fractures were also performed. The pooled RR for 7 studies[4,21,28,30,32–34] related to the vertebral fracture was calculated. The result indicated a significant association between RA and the vertebral fracture (RR = 2.93, 95% CI [2.25–3.83]). Similarly, subgroup analyses of 7 studies[4,19,21,27,29,31,34] with hip fracture outcomes showed that RA is positively correlated with hip fracture (RR = 2.41, 95% CI [1.83–3.17]) (Fig. 3B).
4.5 Sensitivity analysis
Sensitivity analysis was performed to explore the heterogeneity among studies and to determine whether these factors would have an impact on the overall pooled estimates. Our sensitivity analysis showed that no individual studies significantly affected the pooled RRs (Fig. 4).
4.6 Publication bias
The funnel plot showed asymmetry, indicating the presence of potential publication bias (Fig. 5). Further analysis with Egger's test showed no evidence of publication bias (P = .554).
RA is a common chronic inflammatory joint disease in adults. Progression of RA leads to local and systemic bone loss, and patients eventually develop osteoporosis.[4–6] Osteoporosis is a condition in which the bone decreases in strength and becomes vulnerable to fracture. The manifestation of the osteoporosis is due to the loss of bone mass and damage of fine structure in bone tissue which increases bone fragility. Our study, together with other studies,[19–21,35] demonstrate that patients with RA are at higher risk of osteoporotic fractures than patients with non-RA. Postmenopausal women are more prone to osteoporosis and it is estimated that osteoporotic fracture occurs at least once in approximately 50% of postmenopausal women and in over 20% of men over 50 years of age.[36,37] However, our results show a similar increased risk of fracture in men and women with RA than those without RA, further suggesting that RA is an independent risk factor for fracture. Although patients with osteoporosis are prone to fractures mainly in the vertebral, hip, and forearm,[38,39] several studies have argued an increased risk of hip[21,27,29] or vertebral[20,21] fractures in RA patients. Our result show comparable risks of fractures at the vertebral and hip in RA patients, suggesting no specificity in the site fracture.
As fracture often reduces quality of life, fracture prevention is, therefore, crucial for patients with RA. First, the fracture risk should be carefully evaluated in RA patients. Although RA is an independent risk factor for fracture itself, chronic inflammation and glucocorticoid application may promote the development of osteoporosis.[40–42] Therefore, regular bone mineral density (BMD) measurement and fracture risk assessment using tools such as FRAX (Fracture Risk Assessment) algorithm should be performed for early detection of osteoporosis in RA patients.[43,44] Other skeletal or nonskeletal fracture risk factors, as well as other conditions such as age, gender, body mass index, cigarette smoking, high alcohol intake, inadequate physical activity, and family history of osteoporosis, that may lead to reduced BMD should be considered in the evaluation of fracture risk assessment in RA patients. For patients with high fracture risk, and those taking glucocorticoids particularly, prescription of calcium and vitamin D supplements, and treatments to control BMD loss, such as bisphosphonates, denosumab, and parathyloid hormone analogs should be considered.
Second, chronic inflammation in RA should be controlled. For decades, prednisone, a corticosteroid drug, has been widely used to suppress inflammation, but the treatment itself could also enhance BMD loss. Disease-modifying antirheumatic drugs such as methotrexate (MTX) are able to control RA disease activity and could be considered as a treatment option, as current clinic studies did not show the increased risk for osteoporosis and osteoporotic fracture in RA patients treated with MTX. Newer inflammation-fighting drugs, such as TNF inhibitors etanercept and adalimumab, have also been reported to control inflammation without disrupting bone remodeling.[47,48] However, further investigations are warranted, as there are no data available to determine whether TNF inhibitors can minimize the risk for fracture.
Third, patients with RA should be assessed for fall risk regularly. Falls are the leading cause of fracture. More than 95% of hip fractures resulted from falls. Immobility resulting from pain, swelling, and lack of motor coordination in RA patients highly increases their risks of falling, thus increasing the risk for fracture. Taking certain preventive measures may help to reduce fall risk. Tai Chi and regular weight-bearing exercises such as walking and running may strengthen the bone and decrease BMD loss. Home safety assessment and hip protectors may reduce the risk of falling and fracture.
There are a few limitations in our meta-analysis. Heterogeneity was present among the 13 studies. Confounding factors such as age, sex, BMI, and postmenopausal status in RA and non-RA groups were not controlled at the same level. The confounders adjusted for are also different between studies. These differences attribute to a certain degree of bias when combined for the estimation of pooled RR. Moreover, the duration and severity of RA were not considered when selecting subjects. This limitation could lead to the overestimation or underestimation of the associated indicator. In general, the risk of bone fracture increases with the duration and severity of RA. We also did not include BMD as one of our primary outcome of interest due to the limited studies available. The association of RA, osteoporosis, and bone fracture is thus not directly displayed. In addition, the treatment for RA patients was not taken into account in this study. Doses and duration of glucocorticoid might contribute to the difference in outcome measurement. The selection of participants, type of treatments given, confounder adjusted for, and matching factors between RA and non-RA patients are all possible sources contributing to the heterogeneity present among studies.
Our study concludes that RA is a risk factor for bone fracture in men and women, with a comparable risk of fracture at the hip and vertebral. Patients with RA are to be monitored more closely to control bone loss and prevent fracture.
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