Introduction
Rheumatoid arthritis (RA) is a systemic disease with chronic inflammatory joint disease as the main manifestation and can lead to the destruction of cartilage and bone. It is characterized by synovitis, joint destruction, bone loss, and systemic complications [
1]. RA is associated with local and systemic inflammation, which can cause bone loss around the joint, bone erosion, osteoporosis, and fractures. Compared with primary osteoporosis, osteoporosis secondary to RA is more likely to lead to fracture [
2].
At present, the gold standard for the diagnosis of osteoporosis is bone densitometry. Osteoporosis is a systemic bone disease, and bone loss and deterioration of bone tissue structure lead to bone fragility and increase in fracture susceptibility, especially at the hip, spine, and wrist. Therefore, determination of how to screen groups at high risk for osteoporosis early, comprehensively, and accurately is particularly important. Possible risk factors for osteoporosis in RA include age, sex, low body mass index, disease course, disease activity, CCP, rheumatoid factor (RF), and glucocorticoid use. Musculoskeletal ultrasound is a multiplanar, dynamic, and noninvasive examination method that can be used for dynamic evaluation of disease activities. Research shows that ultrasound and MRI show good correlations in the identification of inflammatory soft tissue and bone erosive bone lesions [
3]. Various combinations of joint ultrasound scores can be used to evaluate RA disease activity, but the 7-joint ultrasound score (US7) is the first scoring system combining assessment of synovitis, tenosynovitis, and bone destruction in a comprehensive scoring system [
4]. Moreover, US7 is as sensitive to disease changes as the 78-joint score. The US7 includes 7 joints that are most commonly affected in rheumatoid arthritis. Research shows that the joints that are most affected by local erosive bone changes in RA patients are usually the small joints of the hands and feet [
5]. Local bone erosion and systemic osteoporosis have a common pathological basis; bone loss is mainly related to inflammation and disease activity, which can aggravate systemic bone loss. With the increase in local bone erosion, the bone density of RA patients decreases, and the osteoporosis incidence increases [
6].
To improve the quality of life of patients with rheumatoid arthritis and detect osteoporosis early, it is necessary to develop a valid and reliable model to predict osteoporosis in patients with rheumatoid arthritis. Therefore, this study aimed to establish and verify a reliable prediction model for osteoporosis that could play an important role in the early clinical detection of osteoporosis in patients with rheumatoid arthritis.
Discussion
RA is a chronic inflammatory disease characterized by continuous inflammation of the synovium, joint destruction, bone loss, and systemic complications [
9]. Bone changes in rheumatoid arthritis include periarticular bone erosion, periarticular bone loss, and systemic osteoporosis [
10].
There are many possible risk factors for osteoporosis in RA patients, such as age, female sex, low body mass index, glucocorticoid use (daily dose ≥ 7.5 mg), long disease course, high activity, and CCP [
11].
Our study shows that the osteoporosis group was older and has a longer disease course than the group without osteoporosis; age and disease course were independent risk factors for predicting osteoporosis. Research by Tong shows that age is a risk factor for osteoporosis in RA patients [
12]. The risk of vertebral fracture in RA patients increases by 7.2% for every 1 year of increase in age. Research by Gauri also shows that patients with a longer disease course and higher activity are more likely to suffer from osteopenia and osteoporosis [
13]. Previous studies showed that the use of glucocorticoids and other drugs was an independent risk factor for osteoporosis [
14]. Interestingly, our research results showed that compared with the osteoporosis group and the group without osteoporosis, the osteoporosis group had a longer treatment duration, and there was a weak correlation between the treatment duration and osteoporosis (
r = 0.346,
p < 0.001). The reason for this may be that we have excluded long-term (cumulative dose > 2 years) and high-dose (> 7.5 mg/day) glucocorticoid patients, and many studies show that short-term, low-dose glucocorticoid therapy can stabilize the bone mineral density in early RA with high disease activity [
15].
DAS28 is an important way to evaluate the disease activity of RA. Our research shows that the disease activity of the two groups of patients was different, with the disease activity of osteoporosis group being the higher. DAS28 is an independent predictor of osteoporosis, and disease activity was strongly correlated with osteoporosis (
r = 0.629,
p < 0.001). This indicates that there was a correlation between disease activity and bone loss. Bone mineral density loss occurs in the early stage of RA and increases with the increase of disease activity, which is consistent with the research viewpoints of many scholars [
16,
17]. Research shows that the CRP and ESR values of the osteoporosis groups were higher than the non-osteoporosis group, and there was a moderate correlation with osteoporosis, but CRP and ESR were not independent predictors of osteoporosis; the research of Tomizawa and other scholars also confirm this point [
18].
There are many kinds of autoantibodies in the sera of RA patients, with the most common being CCP and RF. In our study, the CCP were different between the osteoporosis and the group without osteoporosis. Many studies have shown that CCP is associated with local and systemic bone mineral density reduction and osteoclast-mediated bone resorption in RA patients [
19]. For early RA patients, when CCP is positive, high-frequency ultrasound is more likely to find articular cartilage destruction and bone erosion changes [
20]. Our research shows that CCP is a predictor of osteoporosis. Research by Tomizawa showed that CCP is a risk factor not only for joint destruction in RA patients but also for bone loss. It is worth mentioning that although RF is not a predictor of osteoporosis, there were differences between the osteoporosis and the group without osteoporosis, and there was correlation with osteoporosis; the reason may be that the relationship between RF and BMD loss is obviously dose-dependent, and a significant difference was only observed in patients with high levels because high levels of RF enhance the relationship between CCP and bone loss [
21].
All indexes of the US7 score were significantly different between the osteoporosis group and the group without osteoporosis. 7-joint ultrasonic bone erosion (
r = 0.634,
p < 0.001) and US7 total score (
r = 0.624,
p < 0.001) had a strong positive correlation with osteoporosis. Gong’s research on the correlation between systemic osteoporosis and local bone erosion in rheumatoid arthritis patients in China shows that osteoporosis is the early manifestation of RA bone erosion; it has been confirmed that RA is related to a high risk of osteoporosis, and whole body bone density is related to local bone erosion in rheumatoid arthritis patients in China. With the increase in local bone erosion, the bone density of RA patients decreases, and the incidence of osteoporosis increases [
22]. Bone erosion is generally regarded as irreversible, and it is the key result of inflammatory rheumatism, which is related to the severity of disease and deterioration of function [
23]. Elshahaly used X-ray to detect hand and foot bone erosion and study its relationship with hip bone density. The results showed that the hip bone density of rheumatoid arthritis patients with bone erosion was significantly lower than that of patients without bone erosion. The results suggested that focal bone loss in RA was closely related to systemic bone loss [
24]. Numerous studies have shown that the joints most frequently invaded by rheumatoid arthritis are the facet joints; the 2nd metacarpophalangeal joint, 3rd metacarpophalangeal joint, 5th metacarpophalangeal joint, 2nd metatarsophalangeal joint, 5th metatarsophalan-geal joint, and the joints detected by the 7-joint ultrasonic score method are the joints most prone to rheumatoid arthritis bone erosion [
25,
26]. Compared with X-ray detection of hand and foot bone erosion in patients with rheumatoid arthritis, ultrasound detection has the advantage no radioactivity and real-time results, and ultrasound can also detect bone and joint from palmar, dorsal, medial, and lateral angles on the long-axis and short-axis tangent plane. Roux’s research also proved that ultrasound is a reliable way to evaluate bone erosion. The number of RA patients with bone erosion detected by ultrasound is approximately twice that of X-ray examination, especially in early RA [
27].
Many studies have used multiple logistic regression analysis to analyze the risk factors for osteoporosis in RA patients. The results showed that age, course of disease, CCP, and DAS28 were risk factors for osteoporosis in RA patients, which was similar to the results of our study [
28,
29]. With regard to the prediction model of rheumatoid arthritis osteoporosis, Meng’s research used the Asian osteoporosis self-assessment tool (OSTA) to explore the value of the OSTA index in predicting osteoporosis in elderly patients with rheumatoid arthritis in China [
30]. The results of binary logistic regression analysis showed that the Sharp score was an independent risk factor for RA-induced osteoporosis, while the OSTA index was the only protective factor. Aizer’s research used stepwise logistic regression analysis to determine the independent predictors of osteoporosis [
31]. The results showed that the independent predictors were age, female sex, fracture history, steroid use, and the doctor’s assessment of RA activity. Although two scholars have performed regression analysis on rheumatoid arthritis osteoporosis and identified the risk factors for osteoporosis, they have not verified the prediction model. Therefore, our study not only established a prediction model of rheumatoid arthritis osteoporosis but also verified the model. The C-index value for predicting osteoporosis was 0.947 (95% CI = 0.932~0.977) in the internal validation and 0.946 (95% CI = 0.940~0.994) in the external validation. The calibration plot showed good consistency between the deviation corrected prediction and the ideal reference line in both the training set and the verification set. In the decision curve, the model curve in the training set was notably better than the two extreme lines, suggesting that the overall net benefit of the population was good; the verification set also performed well. The verification results show that the model has not only good discrimination and calibration ability but also good clinical applicability.
This study has several limitations. First, this was a single-center study. Although we have verified the model internally and externally in independent cohorts in the same center, the conclusion should be cautious; we will continue to collect data from other centers for further verification. Second, the sample size of this study was small, so we will continue to collect cases and conduct multicenter research and verification in the future. Third, excluding patients with long-term use of drugs that cause osteoporosis (including long-term (cumulative dose > 2 years) or high-dose (> 7.5 mg/day) glucocorticoid use) will influence our results and limit their applicability to other populations. Fourth, the prevalence of rheumatoid arthritis was different from those in other ethnic groups. Therefore, this nomogram requires validation in other ethnic groups’ cohort and may require modification prior to its general use.
In summary, a prediction model based on age, course of disease, DAS28, CCP, and 7-joint ultrasonic bone erosion has good discrimination, calibration, and clinical effectiveness and may become a useful clinical model for predicting osteoporosis risk in patients with rheumatoid arthritis.
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