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Keywords:

  • RHEUMATOID ARTHRITIS;
  • VOLUMETRIC BONE MINERAL DENSITY;
  • MICROSTRUCTURE;
  • CORTICAL POROSITY;
  • HR-PQCT

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Subjects and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References

The purpose of this work was to investigate the volumetric bone mineral density (vBMD), bone microstructure, and mechanical indices of the distal radius in female patients with rheumatoid arthritis (RA). We report a cross-sectional study of 66 middle-aged female RA patients and 66 age-matched healthy females. Areal BMD (aBMD) of the hip, lumbar spine, and distal radius was measured by dual-energy X-ray absorptiometry (DXA). High-resolution peripheral quantitative computed tomography (HR-pQCT) was performed at the distal radius, yielding vBMD, bone microstructure, and mechanical indices. Cortical and trabecular vBMD were 3.5% and 10.7% lower, respectively, in RA patients than controls, despite comparable aBMD. Trabecular microstructural indices were –5.7% to –23.1% inferior, respectively, in RA patients compared to controls, with significant differences in trabecular bone volume fraction, separation, inhomogeneity, and structural model index. Cortical porosity volume and percentage were 128% and 93% higher, respectively, in RA patients, with stress being distributed more unevenly. Fourteen RA patients had exaggerated periosteal bone apposition primarily affecting the ulnovolar aspect of the distal radius. These particular patients were more likely to have chronic and severe disease and coexisting wrist deformity. The majority of the differences in density and microstructure between RA patients and controls did not depend on menstrual status. Recent exposure to glucocorticoids did not significantly affect bone density and microstructure. HR-pQCT provides new insight into inflammation-associated bone fragility in RA. It detects differences in vBMD, bone microstructure, and mechanical indices that are not captured by DXA. At the distal radius, deterioration in density and microstructure in RA patients involved both cortical and trabecular compartments. Excessive bone resorption appears to affect cortical more than trabecular bone at distal radius, particularly manifested as increased cortical porosity. Ulnovolar periosteal apposition of the distal radius is a feature of chronic, severe RA with wrist deformity. © 2013 American Society for Bone and Mineral Research.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Subjects and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References

Rheumatoid arthritis (RA) is an autoimmune disorder with known systemic complications. Patients with RA have an increased risk of insufficiency fracture, particularly of the vertebral bodies and proximal femur.1–3 Increased levels of proinflammatory cytokines, such as tumor necrosis factor alpha, interleukin-1, and interleukin-6, which are characteristic of chronic destructive synovitis, reflect a systemic inflammatory state capable of promoting osteoclastogenesis and bone resorption leading to both local and systemic bone loss and increased fracture risk.4

Estimation of bone strength is usually based on areal bone mineral density (BMD) measurement obtained by dual X-ray absorptiometry (DXA). Areal BMD measures integral BMD (combined trabecular and cortical BMD) and is influenced by bone size. Although fracture risk increases with reduced areal BMD, most osteoporotic fractures in postmenopausal women occur in those with an areal BMD T-score above the diagnostic threshold for osteoporosis.5, 6 In addition, improvement in areal BMD after therapy for osteoporosis explains less than 50% of the reduction in fracture risk.7 For these reasons, there is great interest in investigating other factors that affect bone strength that are not captured by areal BMD. These factors include features such as whole-bone geometry, cortical and trabecular microstructure, and tissue composition.8

High-resolution peripheral quantitative computed tomography (HR-pQCT) is a recently developed noninvasive 3D high-resolution imaging technique that allows quantitative assessment of volumetric BMD and bone structure at the peripheral skeleton (distal radius and distal tibia) with an isotropic resolution of approximately 82 µm. HR-pQCT allows independent evaluation of the cortical and trabecular bone components and their respective microstructural features associated with bone quality.9 HR-pQCT data can be applied to voxel-based micro-finite element (µFE) analysis to obtained estimates of whole-bone or compartmental bone strength.10 HR-pQCT has been applied to assess bone quality in patients with postmenopausal osteoporosis11, 12 as well as other diseases such as type 2 diabetes mellitus,13 chronic renal disease,14 hypoparathyroidism,15 and systemic lupus erythematosus.16

In this study, we utilized HR-pQCT to image the distal radius in female RA patients. We hypothesized that chronic inflammation in RA could lead to deficits in volumetric BMD, bone microstructure, and mechanical property detectable by HR-pQCT, which contribute to reduced bone strength and increased fracture risk. In a female RA cohort and an age-matched healthy female control cohort, we obtained measures of areal BMD from different anatomic sites using DXA as well as measures of volumetric BMD, bone microstructure, and image-based mechanical indices from the distal radius using HR-pQCT.

Subjects and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Subjects and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References

Subjects

For this cross-sectional case-control study, 66 Chinese female patients with a diagnosis of RA were recruited from the outpatient rheumatology clinic of the Prince of Wales Hospital in Hong Kong between August and October 2011. All patients fulfilled the American College of Rheumatology 1987 revised classification criteria for RA17 and were ambulatory at the time of study. Sixty-six age-matched apparently healthy female controls were recruited through word of mouth recommendation from the staff at the Prince of Wales Hospital. Exclusion criteria were as follows: (1) known metabolic disorder that could affect bone metabolism, such as severe renal impairment, defined as a creatinine clearance of less than 30 mL per minute, thyroid or parathyroid disease, and malignancy; (2) receiving treatment that affects bone metabolism such as antiresorptive drugs, calcitonin, thyroid or parathyroid hormone therapy, or hormonal replacement therapy; or (3) pregnancy or breastfeeding. Current or past treatment with glucocorticoids was allowed for patients. The study protocol was approved by the Joint Chinese University of Hong Kong–New Territories East Cluster Clinical Research Ethics Committee, and all participants provided written informed consent.

Demographic and clinical assessment

Demographics and clinical characteristics of the participants were assessed by interview and clinical examination. Demographics included age, body weight, body height, menstrual status, and smoking and drinking status. Menopause was defined as amenorrhea for at least 1 complete year and the age of menopause as the age of the last menstrual flow of any amount. One control subject who had hysterectomy without oophorectomy approximately 1 year prior to the study was not considered postmenopausal. Fracture history of the participants and their first-degree relatives was recorded. Only low-trauma fracture, defined as a fracture arising from trauma which would not normally be expected to result in fracture, such as a fall from less than or equal to standing height, was recorded.

Clinical characteristics of RA recorded were disease duration since onset, disease activity, and disease severity. Disease activity was measured by the Disease Activity Score in 28 Joints, with higher score indicating higher disease activity. Disease severity assessment included the number of deformed joints, the disability index of Health Assessment Questionnaire (0–3 = most functional disability), and the presence of radiographic erosions on the hands and/or wrists. Also recorded were current use of disease-modifying anti-rheumatic drugs (DMARDs), including methotrexate, sulfasalazine, hydroxychloroquine, leflunomide, and azathioprine; current use of biologic agents; and current or past use of glucocorticoids.

DXA assessment

Areal BMD of the hip (total left hip and femoral neck), anteroposterior lumbar spine (L1–L4) and the distal radius of the nondominant arm was performed by a technician certified by International Society of Clinical Densitometry on standard DXA equipment (model Hologic Delphi W; Hologic, Bedford, MA, USA). DXA scan of the distal radius spanned 15 mm in length starting 10 mm proximal from the ulnar tip and extending proximally. Our short-term precision error of areal BMD by DXA, expressed as the coefficient of variance (CV), ranges from 0.72% (at lumbar spine) to 1.5% (at femoral neck), and was based on subjects receiving DXA scanning at the center.18 DXA results were expressed in g/cm2 and T-scores (at femoral neck, total hip, and lumbar spine) calculated with reference to a local population norm.18

HR-pQCT assessment

Bone geometry, volumetric BMD, and microstructure at distal radius of the nondominant arm were studied using HR-pQCT (XtremeCT; Scanco Medical AG, Brüttisellen, Switzerland). The participant's forearm was first immobilized in a carbon fiber cast fixed within the scanner gantry. A dorsal-palmer projection image was obtained to define the tomographic scan region. For the distal radius, the scan region was fixed 9.5 mm proximal from the mid-joint line and spanned 9.02 mm in length, equivalent to a stack of 110 slices.19

HR-pQCT images were evaluated using a standard protocol.19 The entire volume of interest (VOI) was automatically separated into cortical and trabecular components, yielding average overall bone density, and trabecular and cortical volumetric BMD in mg hydroxyapatite (HA)/cm3. Trabecular bone volume fraction (BV/TV) was derived from trabecular density, assuming fully mineralized bone to have a mineral density of 1.2 g HA/cm3. Trabecular volumetric BMD was calculated for two regions: the peripheral region adjacent to the cortex and a central medullary region. 3D ridges (the center points of trabeculae) were identified to assess trabecular microstructure, and the spacing between them was assessed by the distance-transformation method.20 Trabecular number (Tb. N, mm−1) was defined as the inverse mean spacing of the 3D ridges. Trabecular thickness and separation were derived from BV/TV and Tb. N analogous to standard histomorphometry methods. The standard deviation of 1/Tb. N was used to reflect inhomogeneity of trabecular network. The orientation of the trabecular network was quantified using the Structure Model Index (SMI).21 For an ideal plate and rod structure, the SMI value would be 0 and 3, respectively. For a structure with mixed plates and rods of equal thickness, the value lies between 0 and 3, depending on the volume ratio of rods and plates; the closer the SMI to 0, the greater the plate structure, whereas the closer the SMI to 3, the greater the rod structure. Our short-term precision error of volumetric BMD measurement, expressed as CV, ranged from 0.38% to 1.03%, based on another cohort comprising 32 healthy subjects. The short-term reproducibility of microstructural parameters was slightly lower, with CV ranging from 0.80% to 3.73%.

The default cortical bone analysis provided by HR-pQCT performs poorly for subjects with thin or porous cortices.22 Accordingly, a fully automated cortical compartment segmentation technique adapted from the method described by Buie and colleagues22 was used. Based on this segmentation, cortical volumetric BMD was the mean mineralization of all voxels in the cortical VOI. A volumetric index of cortical porosity, denoted Ct. Po (%), was calculated based on the cortical pore volume (Ct. PoV) and the mineralized cortical bone volume (Ct. BV): Ct. Po = Ct. PoV/(Ct. PoV + Ct. BV).23 Other variables related to cortical microstructure included cortical pore diameter and distribution of cortical pore diameter (the SD of cortical pore diameter). In addition, a direct 3D calculation of endosteal-periosteal distance, equal to cortical thickness, was performed on composite segmentations of the mineralized cortex, disregarding intracortical pore surfaces in these calculations.

Image analysis

Representative HR-pQCT images of the distal radius for a median (by trabecular volumetric BMD) RA patient and a median control are shown in Fig. 1. The automated cortical bone compartment segmentation was qualitatively acceptable in all patients and controls except for 14 RA patients in whom focal periosteal bone apposition, recognized by focal expansion of the outer cortical margin beyond its normal boundaries,24 was present, as judged by visual inspection of the images. In these 14 RA patients, in whom separate subgroup analysis was additionally undertaken, there was exaggerated periosteal bone apposition present, leading to undue cortical thickening, together with an exaggerated cortical porosity and an exaggerated endocortical trabecularization (Fig. 2). Due to poor detection of the endocortical boundary, manual adjustment to the endocortical contour was undertaken for these 14 RA patients.

thumbnail image

Figure 1. Representative HR-pQCT images of the distal radius of a median (by trabecular volumetric bone mineral density) control (top) and a median rheumatoid arthritis (RA) patient (bottom): distal-most slices (A, E), proximal-most slice (B, F), 3D visualization of the mineralized cortical bone (transparent gray), cortical porosity (solid red), and trabecular bone (solid green) (C, G), and 3D visualization of cortices (transparent gray) and cortical porosity (solid red) (D, H). The increased cortical porosity in RA patients is particularly noticeable.

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thumbnail image

Figure 2. HR-pQCT images of the distal radius from a representative rheumatoid arthritis patient with exaggerated periosteal bone apposition leading to a change in cortical morphology with an osseous prominence on the ulnovolar aspect of the distal radius (arrows), particularly distally: slice no.25 (A), slice no. 80 (B), and 3D visualization of the cortex (transparent gray) and cortical porosity (solid red) (C, D).

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µFE analysis

All µFE analyses were performed using the FE-solver included in the built-in Image Processing Language software of HR-pQCT. A special peeling algorithm, specifying a minimum cortical thickness of six voxels, was used to identify cortical and trabecular bone tissue. µFE analysis was performed by converting the binary image data to a mesh of isotropic brick elements.25 Different elastic properties were specified for cortical and trabecular bone tissue. For all elements, a Poisson's ratio of 0.3 was specified. Elements representing cortical bone were assigned a Young's modulus of 20 GPa, and those representing trabecular bone tissue were assigned a Young's modulus of 17.5 GPa.26 A uniaxial compression test with a 1000-N load was performed with an applied strain of 1%. Stiffness, apparent modulus, load percentage carried by cortical bone at the distal and proximal surface of the VOI (% load Ct. distal end and % load Ct. proximal end, respectively), and average and SD of von Mises stresses for the trabecular and cortical bone were calculated. Failure load was estimated using methods described by Pistoia and colleagues.27

Statistical analysis

Statistical analyses were performed using the Statistics Package for Social Sciences (SPSS for Windows, version 13.0; SPSS Inc, Chicago, IL, USA). Comparisons in demographics between RA patient and control were analyzed by Student's t test or chi-square test depending on data type. All densitometric, microstructural, and mechanical indices were expressed as mean ± SD and were compared between two groups using Student's t test. The relationship between cumulative glucocorticoid dose and densitometric, microstructural, and mechanical indices was examined by Spearman correlation. Because the body weight of RA patients was statistically lower than that of controls, analysis of covariance was performed for statistical significance with body weight as a covariate. Interactions between body weight and each dependent variable were tested and homogeneity of regression slopes of body weight between groups was assumed. Densitometric, microstructural, and mechanical indices among these 14 particular RA patients with exaggerated periosteal bone apposition, other RA patients, and controls were compared using analysis of variance (ANOVA) with Bonferroni-corrected pairwise comparisons. To examine whether differences between RA patients and controls were driven by menstrual status, two-way ANOVA was performed with groups (RA patients versus controls) and menstrual status (pre- and postmenopause) as independent variables. Results were reported as interactive p values. An interactive p value <0.05 indicated that postmenopausal RA patients differed from postmenopausal controls to a different degree than premenopausal RA patients from premenopausal controls. Two-way ANOVA was also performed to test the interaction between recent exposure to glucocorticoids and menstrual status. All hypotheses were two-tailed, and p values <0.05 were considered statistically significant.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Subjects and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References

Characteristics of study subjects

Characteristics of patients and controls are shown in Table 1. RA patients did not differ significantly from controls in age, body height, menstrual status, age of menopause, years of postmenopause, and smoking and drinking habits. Body weight was significantly lower in RA patients such that adjustment for body weight was added to univariate between-group comparisons. Adjustment for body weight did not change the results significantly (Table 2). Only 1 RA patient had a prior proximal femoral neck insufficiency fracture. In general, the RA cohort comprised patients with mild disease activity and mild functional disability. Thirteen patients had active swollen wrist(s) at the time of study and 22 had deformed wrist(s). Two patients had multiple joint replacements. Most (91%) patients were currently on synthetic DMARDs, while only 5 (8%) patients were currently on biologic agents. Nineteen patients were either currently on oral glucocorticoids (15 patients) or had received glucocorticoids within 6 months prior to the study (4 patients).

Table 1. Characteristics of Study Participants
VariablesRheumatoid arthritis (n = 66)Controls (n = 66)p
  • Results are mean ± SD or median (interquartile range) unless otherwise indicated. Boldface indicates statistically significant difference.

  • a

    At hands and/or wrists, available in 64 patients.

Age (years)48.9 ± 8.248.8 ± 8.20.938
Body weight (kg)55.0 ± 10.558.3 ± 7.30.038
Body height (m)1.56 ± 0.061.56 ± 0.050.604
Postmenopausal, n (%)29 (44)29 (44)
Age at menopause (years)48.0 ± 4.248.6 ± 5.50.641
Postmenopause (years)7.1 (3.0–9.6)3.3 (1.9–8.6)0.116
Current smoker, n (%)4 (6.1)2 (3.0)0.680
Current drinker, n (%)03 (4.5)0.244
Fracture, first-degree relative, n (%)5 (7.6)9 (13.6)0.258
Fracture at age >25 years, n (%)1 (1.5)0
Disease duration since onset (years)8.7 (4.0–15.6)
Disease Activity Score in 28 joints3.1 ± 1.2
Deformed joint(s), n0 (0–3)
 Deformed wrist(s), n (%)22 (33.3)
Health Assessment Questionnaire score0.5 (0–1)
Erosive disease, n (%)a33 (51.6)
Currently on glucocorticoids, n (%)15 (22.7)
 Current dose (prednisolone equivalent) (mg/d)5 (2.5–7.5)
 Cumulative dose (g)3.5 (1.4–8.7)
 Cumulative duration (months)30.4 (11.5–82.6)
Previously on glucocorticoids, n (%)16 (24.2)
 Last use of glucocorticoids (years)3.3 (0.6–12.0)
 Cumulative dose (g)0.7 (0.3–2.2)
 Cumulative duration, months5.5 (2.1–12.5)
Exposure to glucocorticoids 6 months prior to the study, n (%)19 (14.4)
 Cumulative dose (g)2.8 (1.3–7.1)
 Cumulative duration (months)17.8 (5.1–57.9)
Table 2. Densitometric, Microstructural, and Bone Image-Based Mechanical Indices for RA Patients and the Controls
VariablesRA (n = 66)Controls (n = 66)% DifferenceUnadjusted pAdjusted paInteractive pb
  • Results are mean ± SD. Bold indicates statistically significant difference.

  • RA = rheumatoid arthritis; BMD = bone mineral density; vBMD = volumetric bone mineral density; hydroxyapatite = HA; Tb = trabecular; pTb = trabecular bone in the peripheral region adjacent to the cortex; mTb = trabecular bone in the central medullary region; Ct. = cortical; BV/TV = trabecular bone volume fraction; Ct. PoV = cortical pore volume; Ct. Po = cortical porosity index; Ct. Po. Dm = cortical pore diameter; Ct. Po. Dm. SD = standard deviation of Ct. Po. Dm.

  • a

    Values of p are adjusted by body weight.

  • b

    Conducted by two-way ANOVA with groups (RA patients versus controls) and menstrual status (pre- and postmenopause) as independent variables. Interactive p value refers to the significance of the interaction between the two independent variables. An interactive p < 0.05 indicates that postmenopausal RA patients differed from postmenopausal controls to a different degree than the premenopausal RA patients differed from premenopausal controls.

Areal BMD (g/cm2)
 Femoral neck0.70 ± 0.130.72 ± 0.11–2.50.4040.7420.789
 Total hip0.82 ± 0.140.86 ± 0.12–4.00.1320.7730.570
 Lumbar spine (L1–L4)0.93 ± 0.150.96 ± 0.15–3.20.2310.7410.659
 Distal radius0.42 ± 0.080.43 ± 0.06–3.30.2220.4760.226
vBMD (mgHA/cm3)
 Average vBMD357.6 ± 83.5381.1 ± 66.8–6.20.0770.1090.061
 Tb. vBMD122.9 ± 40.3137.7 ± 33.5–10.70.0240.0470.572
 pTb. vBMD188.3 ± 37.5200.2 ± 33.0–6.00.0150.1000.763
 mTb. vBMD77.4 ± 44.694.1 ± 34.9–17.70.0550.0360.496
 Ct. vBMD996.2 ± 79.71033 ± 44–3.50.0010.0010.733
Trabecular architecture
 BV/TV0.10 ± 0.030.11 ± 0.03–10.80.0230.0460.568
 Tb. number (mm−1)1.44 ± 0.331.53 ± 0.23–5.70.0820.2010.101
 Tb. thickness (mm)0.07 ± 0.010.08 ± 0.01–5.90.0830.0780.611
 Tb. separation (mm)0.67 ± 0.200.60 ± 0.1411.40.0250.0490.053
 Inhomogeneity (mm)0.32 ± 0.190.26 ± 0.0823.10.0390.0240.013
 Structure model index2.37 ± 0.432.12 ± 0.4211.80.0010.0010.659
Cortical architecture
 Cortical area fraction0.30 ± 0.070.30 ± 0.06–0.20.9500.9310.042
 Ct. thickness (mm)1.1 ± 0.31.1 ± 0.25.50.1580.0890.041
 Ct. PoV (mm3)16.0 ± 25.27.0 ± 4.5128.00.0060.0030.356
 Ct. Po (%)2.65 ± 2.871.37 ± 0.9693.00.0010.0010.705
 Ct. Po. Dm (mm)0.18 ± 0.030.17 ± 0.028.50.0010.0020.627
 Ct. Po. Dm. SD (mm)0.08 ± 0.020.07 ± 0.0217.30.0010.0020.541
Mechanical indices
 Stiffness (kN/mm)66 ± 1369 ± 12–3.90.2210.5670.443
 Modulus (MPa)2185 ± 4912300 ± 443–5.00.1570.2450.292
 Failure load, n3279 ± 6533456 ± 580–5.10.1020.3180.520
 % Load Ct. distal end68 ± 9.263 ± 8.37.90.0010.0010.200
 % Load Ct. proximal end91.2 ± 5.390.8 ± 4.40.40.6670.7420.183
 Tb. average stress (MPa)45.3 ± 8.349.9 ± 7.7–9.30.0010.0010.456
 Tb. SD stress (MPa)31.5 ± 2.530.7 ± 1.82.40.04970.0550.364
 Ct. average stress (MPa)84.9 ± 3.186.2 ± 2.0–1.50.0060.0070.504
 Ct. SD stress (MPa)18.6 ± 2.317.3 ± 1.37.6<0.0005<0.00050.728
 Tb. equivalent strain8.3E-03 ± 1.4E-039.0E-03 ± 1.2E-03–8.40.0010.0010.465
 Ct. equivalent strain1.40E-02 ± 3.0E-041.41E-02 ± 1.5E-04–0.80.0090.0090.535

Areal BMD

Areal BMD values tended to be lower in RA patients, with the largest percentage difference at the total hip (–4.0%), but these did not differ statistically from controls (Table 2). The prevalence of osteoporosis (T-score ≤ –2.5) at the femoral neck, total hip, and lumbar spine in RA patients was 10.6%, 7.6%, and 7.6%, respectively, whereas in controls, it was 6.1%, 0%, and 4.5%, respectively, with significant difference observed only in the prevalence of osteoporosis at the total hip (p = 0.028).

Volumetric BMD and microstructure

In contrast to areal BMD, volumetric BMD, cortical and trabecular microstructure, and image-based mechanical indices differed significantly between RA patients and controls (Table 2). Cortical (–3.5%) and trabecular volumetric BMD (–10.7%) were significantly lower in RA patients. The average volumetric BMD was also lower in RA patients though this did not reach statistical significance. Difference in trabecular volumetric BMD in the central medullary region between RA patients and controls was more marked (–17.7%) than that in the peripheral region adjacent to the cortex (–6.0%), even after adjustment for body weight.

Trabecular microstructural indices were on average between –5.7% (Tb. N) and –23.1% (trabecular network inhomogeneity) worse in RA patients than controls with significant differences in BV/TV, trabecular separation, and trabecular network inhomogeneity. RA patients also had significantly more rod-like trabeculae than controls, as evidenced by a higher SMI value.

Cortical area fraction and cortical thickness were comparable between RA patients and controls. The most dramatic deterioration in bone microstructure in RA patients was related to cortical porosity. Ct. PoV and Ct. Po were 128% and 93% significantly higher, respectively, in RA patients. Diameters of intracortical pores were significantly higher and large intracortical pores were also more common in RA patients.

Image-based bone strength analyses

Estimates of whole-bone strength using image-based indices of stiffness, modulus, and failure load were lower in RA patients but these differences did not reach statistical significance (Table 2). In both RA patients and controls, most of the load was carried by cortical bone, especially toward the more distal end where the proportionate load carried by cortical bone was significantly higher in RA patients. Cortical and trabecular average stress was lower in RA patients. However, stress variation was greater in RA patients than in controls, as shown by significantly higher cortical SD stress and higher trabecular SD stress, which was marginally greater after adjustment for body weight (p = 0.055) in RA patients. Both cortical and trabecular equivalent strain was lower in RA patients, indicating a compromised bone strength when resisting a compressive load.

Subgroup analyses of RA patients with exaggerated periosteal bone apposition

Fourteen RA patients were indentified with exaggerated periosteal bone apposition. Such patients had significantly longer disease duration, more deformed joints, and were more likely to have erosions in the hands and/or wrists than those without periosteal bone apposition (Table 3). Wrist deformity was the most common joint deformity in this subgroup, being significantly more common (p < 0.0005) than in RA patients without periosteal bone apposition.

Table 3. Characteristics of Rheumatoid Arthritis Patients With Exaggerated Periosteal Bone Apposition and Patients With Preserved Cortical Morphology
VariablesPreserved cortical morphology (n = 52)Exaggerated periosteal bone apposition (n = 14)p
  • Results are mean ± SD or median (interquartile range) unless otherwise indicated. Bold indicates statistically significant difference.

  • a

    At hands and/or wrists, available in 64 patients.

Age (years)48.6 ± 8.650.3 ± 6.70.489
Body weight (kg)54.0 ± 10.857.8 ± 9.20.229
Body height (m)1.56 ± 0.071.58 ± 0.050.133
Postmenopausal, n (%)24 (46)5 (36)0.485
Age at menopause (years)48.0 ± 4.347.8 ± 3.30.900
Postmenopause (years)7.0 (3.0–9.6)7.9 (2.9–11.5)0.776
Disease duration since onset (years)8.2 (3.4, 12.7)14.7 (7.7–19.6)0.004
Disease activity score in 28 joints3.8 ± 1.33.9 ± 1.20.774
Deformed joint(s), n0 (0–3)2.5 (1.8–4.0)0.011
Deformed wrist(s), n (%)11 (21)11 (79)<0.0005
Health Assessment Questionnaire score0.4 (0–1)0.7 (0.1–1.0)0.460
Erosive disease, n (%)a20 (40)13 (93)<0.0005
Currently or previously on glucocorticoids, n (%)25 (48)6 (43)0.728

Image analyses revealed that the exaggerated periosteal bone apposition was exclusively found in the region adjacent to the radioulnar joint and was particularly prominent toward the more distal end of the radius. There were significant differences between RA patients with exaggerated periosteal bone apposition, RA patients without exaggerated periosteal bone apposition, and controls, in areal BMD at distal radius, several trabecular microstructural parameters (trabecular separation, trabecular network inhomogeneity, and SMI), cortical volumetric BMD, all cortical microstructural parameters, and most mechanical indices (Table 4). The significantly higher cortical porosity for the whole RA group was primarily driven by these 14 RA patients who had significantly lower cortical volumetric BMD than patients without periosteal bone apposition or than controls. This difference was largely due to greater Ct. PoV and higher Ct. Po, which were both dramatically higher in this group of patients compared with the other two groups. The higher cortical area fraction and thicker cortex, both most prominent at the more distal end, in this group of patients, led to a significantly larger proportion of load being carried by the cortical bone at the distal end and a lower cortical average stress. However, the load was not evenly distributed through the cortex, and cortical equivalent strain was significantly lower in this group of patients.

Table 4. Densitometric, Microstructural, and Image-Based Mechanical Indices for RA Patients With Exaggerated Periosteal Bone Apposition and Patients With Preserved Cortical Morphology
VariablesPreserved cortical morphology Group 1 (n = 52)Exaggerated periosteal bone apposition Group 2 (n = 14)Group 1 versus Group 2 versus controlsGroup 1 versus Group 2Group 1 versus controlsGroup 2 versus controls
  1. Results are mean ± SD. Bold indicates statistically significant difference.

  2. RA = rheumatoid arthritis; BMD = bone mineral density; vBMD = volumetric bone mineral density; hydroxyapatite = HA; Tb = trabecular; pTb = trabecular bone in the peripheral region adjacent to the cortex; mTb = trabecular bone in the central medullary region; Ct. = cortical; BV/TV = trabecular bone volume fraction; Ct. PoV = cortical pore volume; Ct. Po = cortical porosity index; Ct. Po. Dm = cortical pore diameter; Ct. Po. Dm. SD = standard deviation of Ct. Po. Dm.

Areal BMD (g/cm2)
 Femoral neck0.68 ± 0.120.76 ± 0.170.1090.6160.4490.815
 Total hip0.81 ± 0.130.88 ± 0.170.0610.2070.1251.000
 Lumbar spine (L1–L4)0.92 ± 0.140.98 ± 0.170.1970.5340.3351.000
 Distal radius0.40 ± 0.060.48 ± 0.09<0.0005<0.00050.0300.047
vBMD (mgHA/cm3)
 Average vBMD349.7 ± 82.4387.2 ± 83.90.0540.2970.0771.000
 Tb. vBMD122.5 ± 37.6124.3 ± 50.40.0771.0000.0900.673
 pTb. vBMD185.2 ± 35.3199.6 ± 44.30.0640.5320.0711.000
 mTb. vBMD78.9 ± 41.772.0 ± 55.50.0541.0000.1310.193
 Ct. vBMD1,012.4 ± 67.7935.9 ± 93.6<0.0001<0.00050.214<0.0001
Trabecular architecture
 BV/TV0.10 ± 0.030.10 ± 0.040.0761.0000.0890.656
 Tb. number (mm−1)1.46 ± 0.301.38 ± 0.460.1571.0000.5320.270
 Tb. thickness (mm)0.07 ± 0.010.07 ± 0.020.1110.7110.1261.000
 Tb. separation (mm)0.65 ± 0.190.71 ± 0.220.0420.7610.2500.074
 Inhomogeneity (mm)0.30 ± 0.150.40 ± 0.280.0040.0630.4330.004
 Structure model index2.34 ± 0.432.49 ± 0.420.0020.6900.0190.010
Cortical architecture
 Cortical area fraction0.28 ± 0.060.36 ± 0.06<0.0005<0.00010.3700.002
 Ct. thickness (mm)1.05 ± 0.201.49 ± 0.34<0.0001<0.00011.000<0.0001
 Ct. PoV (mm3)8.5 ± 7.643.6 ± 43.6<0.0001<0.00011.000<0.0001
 Ct. Po (%)1.77 ± 1.605.92 ± 4.08<0.0001<0.00010.693<0.0001
 Ct. Po. Dm (mm)0.17 ± 0.020.20 ± 0.03<0.0001<0.00010.203<0.0001
 Ct. Po. Dm. SD (mm)0.07 ± 0.020.10 ± 0.02<0.0001<0.00050.125<0.0001
Mechanical indices
 Stiffness (kN/mm)64 ± 1175 ± 190.0060.0090.0830.286
 Modulus (MPa)2133 ± 4962376 ± 4340.0830.2530.1621.000
 Failure load (N)3189 ± 5493615 ± 8920.0190.0640.0571.000
 % Load Ct. distal end66.2 ± 8.674.4 ± 9.0<0.00050.0050.123<0.0005
 % Load Ct. proximal end90.5 ± 5.593.8 ± 3.60.0660.0671.0000.107
 Tb. average stress (MPa)45.9 ± 8.043.0 ± 9.50.0020.6860.0220.011
 Tb. SD stress (MPa)31.2 ± 2.432.5 ± 2.40.0230.1640.6820.020
 Ct. average stress (MPa)85.5 ± 3.082.6 ± 2.4<0.00010.0010.435<0.0001
 Ct. SD stress (MPa)17.8 ± 1.721.5 ± 2.0<0.0005<0.00050.201<0.0005
 Tb. equivalent strain8.35E-03 ± 1.30E-037.86E-03 ± 1.63E-030.0020.6050.0210.008
 Ct. equivalent strain1.41E-02 ± 2.60E-041.38E-02 ± 2.85E-04<0.0001<0.00011.000<0.0001

Subgroup analyses by menstrual status, wrist involvement, and use of glucocorticoids

Most of the differences between RA patients and controls did not depend on menstrual status, indicated by the majority of interactive p values >0.05 (Table 1). Postmenopausal patients differed from postmenopausal controls to a similar degree as premenopausal patients differed from premenopausal controls in most densitometric, microstructural, and mechanical indices, except for trabecular network inhomogeneity, cortical area fraction, and cortical thickness. There was a larger percentage difference in trabecular network inhomogeneity between postmenopausal patients and controls (47%) than that between premenopausal patients and controls (3%). Postmenopausal RA patients tended to have lower cortical area fraction (–9%) and thinner cortices (–3%) than their counterparts, whereas premenopausal RA patients had higher cortical area fraction (6%) and thicker cortices (12%) than their counterparts.

There were no significant differences in densitometric, microstructural, and mechanical indices between RA patients with and without active swollen wrist(s) at the time of study (data not shown). Compared with those without deformed wrist, despite small differences in areal BMD, patients with deformed wrist(s) had significantly lower cortical and medullary trabecular volumetric BMD, inferior trabecular microstructural indices, higher Ct. PoV and Ct. Po, lower cortical and trabecular average stresses, but greater stress variation, and lower cortical equivalent strain (Table 5).

Table 5. Densitometric, Microstructural, and Image-Based Mechanical Indices for RA Patients by Wrist Deformity and by Recent Exposure to Glucocorticoids (6 Months Prior to the Study)
VariablesDeformed wrist(s)Recent exposure to glucocorticoidsa
 Yes (n = 22)No (n = 44)pYes (n = 19)No (n = 47)pInteractive pb
  • Results are mean ± SD. Bold indicates statistically significant difference.

  • RA = rheumatoid arthritis; BMD = bone mineral density; vBMD = volumetric bone mineral density; hydroxyapatite = HA; Tb = trabecular; pTb = trabecular bone in the peripheral region adjacent to the cortex; mTb = trabecular bone in the central medullary region; Ct. = cortical; BV/TV = trabecular bone volume fraction; Ct. PoV = cortical pore volume; Ct. Po = cortical porosity index; Ct. Po. Dm = cortical pore diameter; Ct. Po. Dm. SD = standard deviation of Ct. Po. Dm.

  • a

    Nine (47%) and 20 (43%) patients were postmenopausal in the group with and the group without recent exposure to glucocorticoids, respectively.

  • b

    Conducted by two-way ANOVA with recent exposure to glucocorticoids (yes versus no) and menstrual status (pre- and postmenopause) as independent variables. An interactive p value <0.05 indicates that the difference between patients with and without recent exposure of glucocorticoids differs by their menstrual status.

Areal BMD (g/cm2)
 Femoral neck0.68 ± 0.170.71 ± 0.110.5370.69 ± 0.120.70 ± 0.130.8510.268
 Total hip0.79 ± 0.180.84 ± 0.120.3160.80 ± 0.120.83 ± 0.150.4100.204
 Lumbar spine (L1–L4)0.93 ± 0.180.94 ± 0.130.7620.93 ± 0.150.93 ± 0.150.9220.338
 Distal radius0.42 ± 0.100.42 ± 0.060.7260.44 ± 0.060.41 ± 0.080.2550.006
vBMD (mgHA/cm3)
 Average vBMD338.8 ± 88.1367.0 ± 80.50.198376.3 ± 70.3350.1 ± 87.90.2500.011
 Tb. vBMD110.0 ± 45.8129.3 ± 36.00.065126.4 ± 31.5121.5 ± 43.50.6560.045
 pTb. vBMD183.6 ± 42.7190.6 ± 34.90.478188.2 ± 33.7188.3 ± 39.30.9950.049
 mTb. vBMD59.0 ± 50.186.6 ± 39.00.01683.4 ± 31.375.0 ± 49.10.4940.069
 Ct. vBMD946.4 ± 89.41021.1 ± 61.6<0.00051020.0 ± 52.0986.6 ± 87.10.0610.354
Trabecular architecture
 BV/TV0.09 ± 0.040.11 ± 0.030.0630.11 ± 0.030.10 ± 0.040.6470.049
 Tb. number (mm−1)1.33 ± 0.421.50 ± 0.270.04991.50 ± 0.281.42 ± 0.350.3610.418
 Tb. thickness (mm)0.07 ± 0.010.07 ± 0.020.4290.07 ± 0.010.07 ± 0.020.9550.029
 Tb. separation (mm)0.76 ± 0.260.62 ± 0.150.0310.62 ± 0.160.68 ± 0.220.2690.178
 Inhomogeneity (mm)0.41 ± 0.280.27 ± 0.090.0040.30 ± 0.230.33 ± 0.170.6730.591
 Structure model index2.54 ± 0.372.28 ± 0.430.0192.40 ± 0.372.36 ± 0.450.6920.064
Cortical architecture
 Cortical area fraction0.31 ± 0.080.29 ± 0.070.4280.31 ± 0.070.29 ± 0.070.4960.041
 Ct. thickness (mm)1.2 ± 0.41.1 ± 0.20.1781.18 ± 0.221.13 ± 0.320.5640.091
 Ct. PoV (mm3)29.9 ± 37.89.0 ± 10.70.01811.0 ± 9.518.0 ± 29.10.3120.504
 Ct. Po (%)4.50 ± 3.711.72 ± 1.760.0031.92 ± 1.582.94 ± 3.220.1950.785
 Ct. Po. Dm (mm)0.19 ± 0.030.18 ± 0.030.0780.18 ± 0.020.18 ± 0.030.3610.498
 Ct. Po. Dm. SD (mm)0.09 ± 0.020.08 ± 0.020.0960.07 ± 0.020.08 ± 0.020.3950.708
Mechanical indices
 Stiffness (kN/mm)66 ± 1767 ± 120.88570 ± 1265 ± 140.1320.201
 Modulus (MPa)2103 ± 5032225 ± 4850.3452237 ± 4912164 ± 4940.5830.121
 Failure load (N)3222 ± 7893308 ± 5810.6193486 ± 6043196 ± 6590.1030.253
 % Load Ct. distal end71 ± 1066 ± 80.03369.4 ± 10.167.4 ± 8.90.4330.638
 % Load Ct. proximal end92.8 ± 3.290.4 ± 6.00.07692.7 ± 3.090.6 ± 5.90.1520.827
 Tb. average stress (MPa)42.4 ± 7.346.7 ± 8.50.04843.1 ± 7.646.1 ± 8.50.1890.214
 Tb. SD stress (MPa)32.4 ± 2.431.0 ± 2.40.02631.0 ± 1.931.7 ± 2.60.3370.112
 Ct. average stress (MPa)82.7 ± 3.586.0 ± 2.3<0.000185.3 ± 3.584.7 ± 3.00.4920.596
 Ct. SD stress (MPa)20.5 ± 2.417.6 ± 1.5<0.000118.3 ± 2.118.7 ± 2.40.5010.357
 Tb. equivalent strain7.8E-03 ± 1.2E-038.5E-03 ± 1.4E-030.0537.9E-03 ± 1.3E-038.4E-03 ± 1.4E-030.2290.179
 Ct. equivalent strain1.38E-02 ± 3.89E-041.41E-02 ± 1.64E-04<0.00011.41E-02 ± 3.47E-041.40E-02 ± 2.8E-040.3560.503

There were no significant differences in densitometric, microstructural, and mechanical indices between RA patients who were and were not recently exposed to glucocorticoids (6 months prior to the study) (Table 5). For patients with recent exposure to glucocorticoids, cumulative glucocorticoids dose only significantly correlated with trabecular SD stresses (r = 0.502, p = 0.026) and cortical equivalent strain (r = –0.466, p = 0.046). There were interactions between recent exposure to glucocorticoids and menstrual status in average/trabecular volumetric BMD and areal BMD at distal radius, trabecular bone volume fraction, trabecular thickness, and cortical area fraction, suggesting that the differences in these indices between patients who were and were not recently exposed to glucocorticoids differed by their menstrual status (Table 5). Recent exposure to glucocorticoids appeared to be associated with higher average/trabecular volumetric BMD and areal BMD at distal radius, higher trabecular bone volume fraction and cortical area fraction, and thicker trabeculae in postmenopausal patients, whereas the opposite was true in premenopausal patients (Fig. 3).

thumbnail image

Figure 3. Percentage differences in areal bone mineral density (aBMD) at distal radius, average and trabecular volumetric BMD (Tb. vBMD), trabecular vBMD at the peripheral region adjacent to the cortex (pTb.vBMD), trabecular bone volume fraction (BV/TV), trabecular thickness, and cortical area fraction between rheumatoid arthritis patients with and without recent exposure to glucocorticoids (6 months prior to the study) by menstrual status (gray bar: postmenopausal patients; black bar: premenopausal patients).

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Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Subjects and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References

This is the first study to describe microstructural changes occurring at the distal radius in patients with RA. HR-pQCT allows a detailed evaluation of density, microstructure, and bone strength at the distal radius. We found that RA patients had substantially lower volumetric BMD, compromised bone microstructure, and imaged-based mechanical indices at the distal radius compared to controls, despite comparable areal BMD at multiple anatomic sites. These findings provide additional insight into the structural changes accompanying inflammation-associated osteoporosis and bone fragility that are not captured by DXA analysis alone.

The etiology of systematic osteoporosis and insufficiency fracture in RA is multifactorial and includes excessive production of proinflammatory cytokines,28, 29 immobility,30–32 weight loss,1, 30 glucocorticoids use,1, 3 and risk of falling.33 Proinflammatory cytokines activate osteoclasts while impeding osteoblasts such that bone resorption is favored over bone formation.34 The degree of inflammation is related to the magnitude of local or systematic osteoporosis.35 The distal radius site is adjacent to radiocarpal joints and radioulnar joint, both of which are the common sites for synovitis in RA. Although active swollen wrist(s) did not have a significant influence on bone density and microstructure in our study, deformed wrist(s), an indicator of chronic inflammation, was significantly associated with lower volumetric BMD, inferior trabecular and cortical microstructural indices, and several compromised mechanical indices. This finding suggests that alterations in bone density and microstructure at distal radius may be, at least in part, attributable to adjacent joint inflammation. Densitometric and microstructural deterioration at distal radius in RA patients involved both cortical and trabecular compartments. RA patients had lower trabecular volumetric BMD, which was more prominent in the central medullary region, along with more widely- and unevenly-spaced trabeculae. Local stresses were not evenly distributed through the trabecular network. Compromised trabecular bone strength could also be reflected by trabecular shape tending to shift from plates to rods in RA patients, because a rod-like trabecular structure possesses lower mechanical strength than a plate-like trabecular structure.36

The bone quality parameter that most dramatically changed in RA patients was cortical porosity. Cortical bone is particularly relevant to bone strength at the proximal femur and distal radius. Cortical porosity is determined by the number and size of the pores.37, 38 Increasing porosity reduces bone strength because microcracks are prone to be initiated at pores and can propagate more easily through porous cortices.37 The increased bone resorption associated with chronic inflammation in RA appears to have a more deleterious effect on cortical bone than trabecular bone at the distal radius. Trabecular bone has a larger surface/volume ratio than cortical bone and is vulnerable to plate perforation with increased resorptive activity.39 However, when trabecular bone is resorbed, further remodeling becomes self-limiting.40 Conversely, cortical bone remodeling is, in a sense, self-perpetuating, because resorption excavates more surfaces for remodeling activity.37, 40 Even with preserved cortical thickness, the same loads on porous cortices are effectively imposed on a reduced cortical bone volume, with loads being unevenly distributed, predisposing to microcracks, and, ultimately, fracture.

The majority of differences in density, microstructure, and mechanical indices between RA patients and controls did not depend on their menstrual status. Postmenopausal and premenopausal RA patients differed from their respective counterparts to a similar degree for most indices. However, endogenous estrogen appeared to protect premenopausal RA patients from a further worsening in a few microstructural indices, including trabecular network inhomogeneity, cortical area fraction, and cortical thickness. Recent exposure to glucocorticoids was not significantly associated with inferior densitometric, microstructural, or mechanical indices in this study. A higher cumulative glucocorticoid dose significantly correlated only with a larger variation of trabecular bone stress and a lower cortical equivalent strain. The net effect of glucocorticoids on bone in RA patients is difficult to determine. There are a few studies suggesting that although low-dose glucocorticoids may rapidly decrease markers for bone formation, predisposing subjects to increased bone fragility,41 they also counteract the effect of inflammation on bone and slow the rate of bone loss adjacent to sites of synovitis.42, 43 We found interactions between recent exposure to glucocorticoids and menstrual status in several densitometric and microstructural indices. However, endogenous estrogen did not seem to protect patients from a further worsening in bone density and microstructure. On the contrary, recent exposure to glucocorticoids appeared to be associated with higher trabecular density and several better microstructural indices in postmenopausal patients, possibly reflecting a more favorable response to the anti-inflammatory effect of glucocorticoids.

In contrast to clear differences in volumetric BMD and microstructure between RA patients and controls revealed by HR-pQCT, very little difference in areal BMD was detected by DXA at most sites used to diagnosis osteoporosis, including the distal radius. The only areal BMD measure indicating impaired bone quality in RA patients was the significantly higher prevalence of osteoporosis when total hip areal BMD was applied. Such lack of distinction can be partly explained by the characteristics of our RA cohort, which had a relatively short disease duration, mild disease activity, and preserved physical function, because osteoporosis in RA is significantly associated with disease activity and severity.35 The inability of areal BMD to detect compartmental differences in bone density and structure is also contributory.44 Our results show how HR-pQCT detects differences in volumetric BMD and bone microstructure and strength indices that accompany inflammation-associated bone loss in RA patients, and which are not captured by DXA.

The high resolution of HR-pQCT allows analysis of subtle changes in bone macro- and microstructure. Another new and interesting finding of our study is that 14 RA patients were found to have exaggerated periosteal bone apposition, extensive endocortical trabeculation, and cortical porosity, primarily affecting the ulnovolar aspect of the distal radius, a bone area close to the distal radioulnar joint. Periosteal apposition results from a net bone accretion on the periosteal surface. Similar changes in cortical morphology have been demonstrated in a rabbit animal model with experimentally-induced inflammatory arthritis, in which the metaphyseal femoral cortex underwent net bone resorption on the anterior cortex and net bone apposition on the posteromedial cortex.45 More global periosteal apposition has been demonstrated in the lumbar vertebral bodies as an adaptive response to reduced BMD in senile osteoporosis.24 In the current study, it was seen that patients with periosteal bone apposition were found to have more chronic and more severe RA with a higher likelihood of wrist deformity. Deformity of the distal radioulnar joint or radiocarpal joints, together with prolonged immobility, might alter local biomechanics, stimulating bone deposition particularly in that area of the distal radius close to the radioulnar joint.

Our study has the following limitations. First, the short-term precision of HR-pQCT to image volumetric BMD and microstructure at the distal radius was obtained from another cohort consisting of healthy subjects. We did not evaluate the precision of HR-pQCT in imaging RA patients although hand positioning seemed generally acceptable. Second, only the distal radius was imaged and not the distal tibia, which can also be assessed by HR-pQCT.11 Although our findings that deformed wrist(s) were associated with a higher degree of deterioration in density and microstructure suggested a contributory role of local inflammation, it would be informative to compare findings at the distal radius and distal tibia, sites not commonly involved in RA, to differentiate the relative effect of local and systemic inflammation. Third, laboratory assessment of proinflammatory cytokines and makers of bone metabolism was not performed. Fourth, although we did not find a significant effect of glucocorticoids on bone density or microstructure, this should not be regarded as a compelling argument for glucocorticoid use in RA, given the relatively small number of patients with recent exposure to glucocorticoids in our study. Also, as a result of the small number of patients in each subgroup, the influence of menstrual status on the effect of glucocorticoids could not be examined in detail. Fifth, direct comparison between areal and volumetric BMD at distal radius was limited because the two scan regions were not identical, though they largely overlapped each other. Sixth, because only one patient had a prevalent insufficiency fracture, our results did not address fracture risk. Seventh, identification of the 14 RA patients with exaggerated periosteal bone apposition relied only on visual image assessment. Finally, because our study comprised a relatively small sample with a cross-sectional design, the causal relationship between inflammation and impaired bone quality could not be established.

In conclusion, using HR-pQCT, we investigated differences in cortical and trabecular density, microstructure, and image-based mechanical indices in female RA patients. RA patients had substantially lower volumetric BMD and inferior microstructure and bone strength indices at the distal radius, despite comparable areal BMD, than controls. Higher cortical porosity was particularly noticeable in RA patients. Recent exposure to glucocorticoids did not affect bone density and microstructure significantly. Our results provide new information on the structural changes that accompany bone fragility in chronic inflammatory disorders. Increased bone remodeling, especially increased bone resorptive activity, produces greater deficits in cortical than trabecular bone at the distal radius. Prominent periosteal bone apposition, particularly on the ulnovolar aspect of the distal radius, is a feature of RA patients with chronic and severe disease. These findings warrant a more detailed study, employing a larger controlled cross-sectional cohort as well as a prospective design, to determine their relationships to bone fragility and fracture risk.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Subjects and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References

This work was supported by Dr. Arthur LS Lui, Providence Foundation Ltd. Dr. Arthur LS Lui, Providence Foundation Ltd had no role in the study design, data collection, data analysis, and production of the manuscript. The authors independently interpreted the results and made the final decision to submit the manuscript for publication.

Authors' roles: All authors were responsible for study design, the collection, analysis and interpretation of all data, the writing of the article, and the decision to publish.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Subjects and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References
  • 1
    van Staa TP, Geusens P, Bijlsma JW, Leufkens HG, Cooper C. Clinical assessment of the long-term risk of fracture in patients with rheumatoid arthritis. Arthritis Rheum. 2006;54(10):310412.
  • 2
    Huusko TM, Korpela M, Karppi P, Avikainen V, Kautiainen H, Sulkava R. Threefold increased risk of hip fractures with rheumatoid arthritis in Central Finland. Ann Rheum Dis. 2001;60(5):5212.
  • 3
    Orstavik RE, Haugeberg G, Mowinckel P, Hoiseth A, Uhlig T, Falch JA, Halse JI, McCloskey E, Kvien TK. Vertebral deformities in rheumatoid arthritis: a comparison with population-based controls. Arch Intern Med. 2004;164(4):4205.
  • 4
    Redlich K, Smolen JS. Inflammatory bone loss: pathogenesis and therapeutic intervention. Nat Rev Drug Discov. 2012;11(3):23450.
  • 5
    Schuit SC, van der Klift M, Weel AE, de Laet CE, Burger H, Seeman E, Hofman A, Uitterlinden AG, van Leeuwen JP, Pols HA. Fracture incidence and association with bone mineral density in elderly men and women: the Rotterdam Study. Bone. 2004;34(1):195202.
  • 6
    Marshall D, Johnell O, Wedel H. Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. BMJ. 1996;312(7041):12549.
  • 7
    Delmas PD, Seeman E. Changes in bone mineral density explain little of the reduction in vertebral or nonvertebral fracture risk with anti-resorptive therapy. Bone. 2004;34(4):599604.
  • 8
    Seeman E, Delmas PD. Bone quality—the material and structural basis of bone strength and fragility. N Engl J Med. 2006;354(21):225061.
  • 9
    Dambacher MA, Neff M, Radspieler HT, Rueegsegger P, Qin L. In vivo bone mineral density structures in humans: from Instom over Densiscan to XtremCT.: In: Qin L, Genant HK, Griffith JF, Leung KS, editors Advanced bioimaging technologies in assessment of quality of bone and scaffold biomaterials. Berlin: Springer-Verlag; p 6578. 2007.
  • 10
    Boutroy S, Van Rietbergen B, Sornay-Rendu E, Munoz F, Bouxsein ML, Delmas PD. Finite element analysis based on in vivo HR-pQCT images of the distal radius is associated with wrist fracture in postmenopausal women. J Bone Miner Res. 2008;23(3):3929.
  • 11
    Stein EM, Liu XS, Nickolas TL, Cohen A, Thomas V, McMahon DJ, Zhang C, Yin PT, Cosman F, Nieves J, Guo XE, Shane E. Abnormal microarchitecture and reduced stiffness at the radius and tibia in postmenopausal women with fractures. J Bone Miner Res. 2010;25(12):257281.
  • 12
    Sornay-Rendu E, Boutroy S, Munoz F, Delmas PD. Alterations of cortical and trabecular architecture are associated with fractures in postmenopausal women, partially independent of decreased BMD measured by DXA: the OFELY study. J Bone Miner Res. 2007;22(3):42533.
  • 13
    Burghardt AJ, Issever AS, Schwartz AV, Davis KA, Masharani U, Majumdar S, Link TM. High-resolution peripheral quantitative computed tomographic imaging of cortical and trabecular bone microarchitecture in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2010;95(11):504555.
  • 14
    Bacchetta J, Boutroy S, Vilayphiou N, Juillard L, Guebre-Egziabher F, Rognant N, Sornay-Rendu E, Szulc P, Laville M, Delmas PD, Fouque D, Chapurlat R. Early impairment of trabecular microarchitecture assessed with HR-pQCT in patients with stage II-IV chronic kidney disease. J Bone Miner Res. 2010;25(4):84957.
  • 15
    Rubin MR, Dempster DW, Kohler T, Stauber M, Zhou H, Shane E, Nickolas T, Stein E, Sliney J Jr, Silverberg SJ, Bilezikian JP, Muller R. Three dimensional cancellous bone structure in hypoparathyroidism. Bone. 2010;46(1):1905.
  • 16
    Li EK, Zhu TY, Tam LS, Hung VW, Griffith JF, Li TK, Li M, Wong KC, Leung PC, Kwok AW, Qin L. Bone microarchitecture assessment by high-resolution peripheral quantitative computed tomography in patients with systemic lupus erythematosus taking corticosteroids. J Rheumatol. 2010;37(7):14739.
  • 17
    Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, Healey LA, Kaplan SR, Liang MH, Luthra HS, Medsger TA Jr, Mitchell DM, Neustadt DH, Pinals RS, Schaller JG, Sharp JT, Wilder RL, Hunder GG. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31(3):31524.
  • 18
    Lynn HS, Lau EM, Au B, Leung PC. Bone mineral density reference norms for Hong Kong Chinese. Osteoporos Int. 2005;16(12):16638.
  • 19
    Boutroy S, Bouxsein ML, Munoz F, Delmas PD. In vivo assessment of trabecular bone microarchitecture by high-resolution peripheral quantitative computed tomography. J Clin Endocrinol Metab. 2005;90(12):650815.
  • 20
    Hildebrand T, Ruegsegger P. A new method for the model-independent assessment of thickness in three-dimensional images. J Microsc. 1997;185(1):6775.
  • 21
    Hildebrand T, Ruegsegger P. Quantification of bone microarchitecture with the structure model index. Comput Methods Biomech Biomed Engin. 1997;1(1):1523.
  • 22
    Buie HR, Campbell GM, Klinck RJ, MacNeil JA, Boyd SK. Automatic segmentation of cortical and trabecular compartments based on a dual threshold technique for in vivo micro-CT bone analysis. Bone. 2007;41(4):50515.
  • 23
    Burghardt AJ, Buie HR, Laib A, Majumdar S, Boyd SK. Reproducibility of direct quantitative measures of cortical bone microarchitecture of the distal radius and tibia by HR-pQCT. Bone. 2010;47(3):51928.
  • 24
    Seeman E. Pathogenesis of bone fragility in women and men. Lancet. 2002;359(9320):184150.
  • 25
    van Rietbergen B, Weinans H, Huiskes R, Odgaard A. A new method to determine trabecular bone elastic properties and loading using micromechanical finite-element models. J Biomech. 1995;28(1):6981.
  • 26
    Turner CH, Rho J, Takano Y, Tsui TY, Pharr GM. The elastic properties of trabecular and cortical bone tissues are similar: results from two microscopic measurement techniques. J Biomech. 1999;32(4):43741.
  • 27
    Pistoia W, van Rietbergen B, Lochmuller EM, Lill CA, Eckstein F, Ruegsegger P. Estimation of distal radius failure load with micro-finite element analysis models based on three-dimensional peripheral quantitative computed tomography images. Bone. 2002;30(6):8428.
  • 28
    Romas E, Gillespie MT. Inflammation-induced bone loss: can it be prevented?. Rheum Dis Clin North Am. 2006;32(4):75973.
  • 29
    Haugeberg G. Focal and generalized bone loss in rheumatoid arthritis: separate or similar concepts?. Nat Clin Pract Rheumatol. 2008;4(8):4023.
  • 30
    Hooyman JR, Melton LJ 3rd, Nelson AM, O'Fallon WM, Riggs BL. Fractures after rheumatoid arthritis. A population-based study. Arthritis Rheum. 1984;27(12):135361.
  • 31
    Michel BA, Bloch DA, Wolfe F, Fries JF. Fractures in rheumatoid arthritis: an evaluation of associated risk factors. J Rheumatol. 1993;20(10):16669.
  • 32
    Nampei A, Hashimoto J, Koyanagi J, Ono T, Hashimoto H, Tsumaki N, Tomita T, Sugamoto K, Nishimoto N, Ochi T, Yoshikawa H. Characteristics of fracture and related factors in patients with rheumatoid arthritis. Mod Rheumatol. 2008;18(2):1706.
  • 33
    Kaz Kaz H, Johnson D, Kerry S, Chinappen U, Tweed K, Patel S. Fall-related risk factors and osteoporosis in women with rheumatoid arthritis. Rheumatology (Oxford). 2004;43(10):126771.
  • 34
    Abdulghani S, Caetano-Lopes J, Canhao H, Fonseca JE. Biomechanical effects of inflammatory diseases on bone-rheumatoid arthritis as a paradigm. Autoimmun Rev. 2009;8(8):66871.
  • 35
    Broy SB, Tanner SB. FRAX® Position Development Conference Members. Official Positions for FRAX® Clinical Regarding Rheumatoid Arthritis, Joint Official Positions Development Conference of the International Society for Clinical Densitometry and International Osteoporosis Foundation on FRAX®. J Clin Densitom. 2011;14(3):1849.
  • 36
    Ding M, Odgaard A, Danielsen CC, Hvid I. Mutual associations among microstructural, physical and mechanical properties of human cancellous bone. J Bone Joint Surg Br. 2002;84(6):9007.
  • 37
    Szulc P, Seeman E. Thinking inside and outside the envelopes of bone: dedicated to PDD. Osteoporos Int. 2009;20(8):12818.
  • 38
    Martin TJ, Seeman E. Bone remodelling: its local regulation and the emergence of bone fragility. Best Pract Res Clin Endocrinol Metab. 2008;22(5):70122.
  • 39
    Parfitt AM. Misconceptions (2): turnover is always higher in cancellous than in cortical bone. Bone. 2002;30(6):8079.
  • 40
    Bjornerem A, Ghasem-Zadeh A, Bui M, Wang X, Rantzau C, Nguyen TV, Hopper JL, Zebaze R, Seeman E. Remodeling markers are associated with larger intracortical surface area but smaller trabecular surface area: a twin study. Bone. 2011;49(6):112530.
  • 41
    Ton FN, Gunawardene SC, Lee H, Neer RM. Effects of low-dose prednisone on bone metabolism. J Bone Miner Res. 2005;20(3):46470.
  • 42
    Haugeberg G, Strand A, Kvien TK, Kirwan JR. Reduced loss of hand bone density with prednisolone in early rheumatoid arthritis: results from a randomized placebo-controlled trial. Arch Intern Med. 2005;165(11):12937.
  • 43
    Ibanez M, Ortiz AM, Castrejon I, Garcia-Vadillo JA, Carvajal I, Castaneda S, Gonzalez-Alvaro I. A rational use of glucocorticoids in patients with early arthritis has a minimal impact on bone mass. Arthritis Res Ther. 2010;12(2):R50.
  • 44
    Griffith JF, Genant HK. Bone mass and architecture determination: state of the art. Best Pract Res Clin Endocrinol Metab. 2008;22(5):73764.
  • 45
    Bogoch E, Gschwend N, Bogoch B, Rahn B, Perren S. Changes in the metaphysis and diaphysis of the femur proximal to the knee in rabbits with experimentally induced inflammatory arthritis. Arthritis Rheum. 1989;32(5):61724.