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Rheumatoid arthritis (RA) is a chronic inflammatory disorder characterized by local and systemic bone loss caused by increased bone resorption. Proinflammatory cytokines and antibodies directed against citrullinated proteins, which are found in two-thirds of RA patients, are considered as central triggers for enhanced bone resorption in RA patients by inducing receptor activator of NF-κB ligand (RANKL) expression, enhancing the number of osteoclast precursors, and stimulating osteoclast differentiation.[2-4] In addition, general risk factors, such as low vitamin D level, postmenopausal state, and immobilization further exacerbate bone disease in patients with RA. Together, these factors result in rapid loss of bone mass at periarticular and nonperiarticular sites including the femoral head and the spine.[7, 8] In addition, RA is considered an independent risk factor for secondary osteoporosis and osteoporosis-related vertebral and nonvertebral fractures,[9-12] which is also reflected by its inclusion into the fracture risk assessment tool (FRAX).
Less is known about micro-architectural changes of cortical and trabecular bone in RA. High-resolution peripheral quantitative computed tomography (HR-pQCT) has been previously validated for the assessment of volumetric bone mineral density (vBMD), bone microstructure, and bone geometry. Moreover, HR-pQCT allows the detection of inflammation-caused periarticular bone changes such as bone erosion and bony proliferation at different skeletal sites.[15, 16] Differences in vBMD and microstructure between Chinese women with RA and healthy control subjects were recently introduced. However, bone density, geometry, trabecular and cortical microstructure, as well as fracture incidence in the Asian population is not comparable to the white population.[18, 19]
Not only inflammation but also treatment modalities influence bone quality in RA. On one hand, glucocorticoids are well known to have adverse effects on the bone, and effect of glucocorticoid treatment on bone fragility has been recently demonstrated in experimental arthritis models. On the other hand, their potent anti-inflammatory potential partly counteracts the negative effects on bone metabolism.[7, 22] Furthermore, disease-modifying antirheumatic drugs (DMARDs) and biologic agents are established therapies for reducing RA joint damage and are widely used in daily clinical practice. Some of these were reported to arrest bone loss[6, 23] or even to increase bone mineral density. However, their influence on bone microstructure and geometry in humans remains unclear.
Therefore, the aim of the present study was to investigate the impact of chronic inflammation and antirheumatic drugs including glucocorticoids, DMARDs, and biologics on bone structure, density, and geometry—three main components of bone strength—in male and female patients with RA.
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In the present study, we demonstrate differences in volumetric bone mineral density, microstructure, and geometry at the periarticular and nonperiarticular radius in RA patients when compared with healthy, age- and sex-related controls. Volumetric BMD was decreased at both trabecular and cortical sites in patients with RA. Low trabecular bone volume was mainly caused by decreased number of trabeculae in female and by trabecular thinning in male RA patients. These changes were reported to be typical sex- and age-related features of trabecular bone loss in males and females, respectively, indicating an accelerated bone aging in patients with RA. The reduction in trabecular number, in particular, has a higher impact on bone strength compared with trabecular thickness. Association between low trabecular number at the distal radius, assessed by HR-pQCT, and prevalent fractures were reported in both men and women.[31, 32] Moreover, in the study of Bréban and colleagues, trabecular bone score (TBS), measured at the lumbar spine, was significantly decreased in RA patients with vertebral fractures compared with those without fractures. Nonetheless, the relation of microstructural changes to increased fracture risk remains to be determined in RA patients. In our study, individual micro-architectural parameters were unable to discriminate between RA patients with and without fractures, which may suggest that more complex deteriorations of bone microstructure, bone mineral density, and bone geometry are responsible for determining fracture risk.
Not only trabecular but also geometric and microstructural properties of cortical bone contribute to bone strength. Thus, cortical bone is a major component to resist axial load. The association between cortical thickness at the radius and prevalent fractures was published previously.[31, 32] In the present study, cortical thickness and cortical volumetric BMD were significantly decreased in male and female RA patients when compared with healthy controls. Aside from age, height, and sex, DMARD intake was also associated with changes in cortical thickness in patients with RA. In addition, cortical porosity was reported to influence bone strength. Indeed, cortical porosity was significantly increased in male RA patients compared with controls in this study. However, after excluding two outliers, the significance disappeared. In addition, cortical porosity was comparable in female RA patients and female controls. In contrast, Zhu and colleagues reported that cortical porosity is the most dramatic deterioration in microstructure measured by HR-pQCT in Chinese women with RA. However, they also concede that the higher cortical porosity in RA was linked to a few patients with exaggerated periosteal bone apposition, which could result from secondary osteoarthritis in these patients. When those patients were excluded, values were comparable between RA and controls. It has to be considered that interpretation of cortical porosity in case of exaggerated periosteal bone apposition is challenging and prone to bias because bone quality of hypertrophic periosteal bone is still unknown. Moreover, using a different analysis algorithm average porosity in the cortex as measured by HR-pQCT was recently reported to be much higher than in studies such as ours using the manufacturer-provided analysis algorithm. Additionally, the resolution of HR-pQCT is insufficient to detect smaller pores in cortex, and precision errors resulting from motional artefacts, especially at the radius, are higher for cortical porosity than for BMD. Therefore, the overall porosity may be at least partly reflected by decreased cortical volumetric BMD, and data on cortical porosity obtained with HR-pQCT should be interpreted with caution.
We confirm the findings of Zhu and colleagues regarding the changes of the volumetric BMD, bone volume, and inhomogeneity of the trabecular network in RA. Conversely, cortical thickness was strongly reduced in our white RA patients but apparently similar in Chinese women with RA compared with respective healthy controls. Marked ethnic differences in trabecular and especially cortical bone between Asian and white people were reported. Chinese-American women have thicker, denser cortices but reduced total cross-sectional area compared with white women, suggesting a compensatory mechanism to counteract fewer trabeculae and smaller bone diameters in the Asian population. Also, thicker trabeculae have been reported for young Chinese and Chinese-American women compared with white women.[18, 19] Moreover, less porosity has been detected in Asian compared with white bone. Chevalley and colleagues recently reported an association between reduction in cortical thickness and cortical vBMD at the distal radius with fractures in young healthy women. In their study, cortical porosity was low and did not differ between women with fracture and without fracture, indicating a more important role of cortical density and thickness than cortical porosity concerning bone strength.
It is known from investigations in juvenile arthritis patients that inflammation can change bone geometry. In the present study, cortical perimeter was enlarged at the distal and ultradistal radius in males and females with RA compared with respective controls. Cortical thinning with periosteal apposition reflected by increased cortical perimeter, as found in our study, is a physiological process to restore bone strength. This mechanism seems to be accelerated by inflammation-related endosteal bone resorption in RA. Thus, an increase in outer circumference by periosteal bone formation could be explained as a compensatory mechanism to counteract cortical thinning and to improve mechanical properties.[41, 43] This hypothesis is also supported by the findings of Aberli and colleagues. In their pQCT study in female RA patients, comparable results to ours regarding bone geometry, including decreased cortical thickness with compensatory increase of the outer bone diameter and cross-sectional area at the radius, were found when compared with healthy controls. Apart from cortical thinning and the increase in cortical perimeter, deformities of bone shape were also observed in the RA patients in our study. However, these deformities do not occur in all patients with RA, and currently there is no validated technique available for quantifying these deformities.
Biological agents such as TNF-alpha-inhibitors were reported to arrest bone loss in RA.[6, 23] However, a specific benefit on prevention of osteoporosis or fractures has not yet been shown.[44, 45] Furthermore, little is known about the influence of conventional DMARDs. Data on MTX are conflicting, and the influence of leflunomide on bone remains unclear. In the present study, current DMARDs intake was associated with an increased cortical perimeter and smaller cortical thickness at the distal radius. In contrast, biological agents were associated with decreased cortical perimeter. Neither conventional DMARDs nor biological agents influenced bone structure and geometry at the periarticular bone. It has to be considered that modification of treatment modalities in RA is common. However, no association was found between number of conventional DMARDs and biological agents ever used and microstructure parameters (data not shown). This suggests an even more important role of inflammation, age, and sex than conventional and biological DMARDs on bone microstructure. However, no negative effects were found for DMARDs on bone. A valuable explanation for the lack of association between DMARDs and microstructure could also be the limited resolution of HR-pQCT.
Glucocorticoids are well known to have adverse effects on bone. An association between glucocorticoids and nonvertebral fracture risk in patients with RA was reported recently. In our multiregression model, high-dose glucocorticoids were associated with cortical thinning, which was in accordance with previous findings, suggesting an increased endosteal bone resorption. Moreover, an association between glucocorticoids and low bone volume fraction and trabecular number was found in the ultradistal radius, although these differences did not reach statistical significance. No effects were found for low-dose glucocorticoids on bone, suggesting that the anti-inflammatory effect of low-dose glucocorticoids counteracts its negative effects on skeleton.
One of the strengths of this study is the assessment of bone composition at two different anatomical sites in both healthy and diseased individuals. Stunningly, the differences between the measurements obtained at the distal radius and the ultradistal radius were similar in RA and in healthy controls and characterized by increased cortical thinning, decreased total bone density, and increased cortical perimeter at the more distal site. Apart from this study, dual-energy X-ray absorptiometry (DXA) and quantitative ultrasound (QUS) have been used to evaluate bone characteristics of the distal radius in patients with RA. In the study of Madsen and colleagues, significant differences in QUS measures were found between RA and healthy controls. Correlations between DXA results of the spine and the hip and bone erosions as well as volumetric BMD in the HR-pQCT were also reported. Interestingly, this latter study showed no association between the bone changes and the actual disease activity and functional state of the RA patients, measured by DAS28 and HAQ score, respectively, which was also confirmed by our study (data not shown). This observation could be based on the limitations of momentary compared with long-term recording of disease activity and function in these studies.
In summary, both trabecular and cortical bone are severely affected in RA (Fig. 4). We found a decreased trabecular bone volume caused by decrease in number and width of the bony trabeculae in female and male RA patients, respectively. Moreover, cortical thinning but not cortical porosity was common in RA. However, micropores in RA, not detected by HR-pQCT, could be the cause for the low cortical vBMD, as found in the present study. The increase in cortical perimeter in RA may reflect a compensatory mechanism to counteract cortical thinning and to restore bone strength. A strong influence of conventional and biological DMARDs on the bone could not be demonstrated. Thus, our data suggest that bone quantity and quality are significantly decreased in the appendicular skeleton of RA patients at both periarticular and nonperiarticular sites.
Figure 4. Cortical and trabecular bone changes in rheumatoid arthritis. Schematic drawing of bone changes in patients with rheumatoid arthritis over time. Factors determining the key changes in bone geometry, volumetric bone mineral density, and bone microstructure are indicated.
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