Bone loss. Quantitative imaging techniques for assessing bone mass in rheumatoid arthritis

Osteoporosis is associated with low bone mass and microarchitectural deterioration of bone tissue with clinical manifestation of low trauma fractures. Rheumatoid arthritis (RA) is a risk factor due to generalized and articular bone loss. This minireview presents past and current bone mass measurement techniques in RA. These techniques include: plain radiographs, absorptiometry, quantitative computed tomography (QCT) and ultrasound. The most widely used technique is dual x-ray absorptiometry (DXA). RA patients have lower bone mass as compared with normals and substantial bone loss may occur early after the onset of disease. Measurement of bone mineral density (BMD) at the hand using either DXA or ultrasound maybe a useful tool in the management of RA patients.     

Bone loss: Therapeutic approaches for preventing bone loss in inflammatory arthritis

Inflammatory arthritides are commonly characterized by localized and generalized bone loss. Localized bone loss in the form of joint erosions and periarticular osteopenia is a hallmark of rheumatoid arthritis, the prototype of inflammatory arthritis. Recent studies have highlighted the importance of receptor activator of nuclear factor-κB ligand (RANKL)-dependent osteoclast activation by inflammatory cells and subsequent bone loss. In this article, we review the pathogenesis of inflammatory bone loss and explore the possible therapeutic interventions to prevent it.     

Inflammatory cells and bone loss in rheumatoid arthritis

Pathogenic bone erosion is often associated with inflammation. The destructive bone erosion that is often seen in rheumatoid arthritis is probably due to the close proximity of inflamed tissues to bone. Over the past decade, major advances have been made in our understanding of the factors that are crucial in regulating osteoclast bone resorption. It is not surprising that these factors are expressed by inflammatory cells that are present in the rheumatoid joint. It now appears that we can add neutrophils to the list of inflammatory cells found in the inflamed rheumatoid joint that express factors that regulate bone erosion.     

Molecular imaging of rheumatoid arthritis: emerging markers,tools, and techniques

Early diagnosis and effective monitoring of rheumatoid arthritis (RA) are important for a positive outcome. Instant treatment often results in faster reduction of inflammation and, as a consequence, less structural damage. Anatomical imaging techniques have been in use for a long time, facilitating diagnosis and monitoring of RA. However, mere imaging of anatomical structures provides little information on the processes preceding changes in synovial tissue, cartilage, and bone. Molecular imaging might facilitate more effective diagnosis and monitoring in addition to providing new information on the disease pathogenesis. A limiting factor in the development of new molecular imaging techniques is the availability of suitable probes. Here, we review which cells and molecules can be targeted in the RA joint and discuss the advances that have been made in imaging of arthritis with a focus on such molecular targets as folate receptor, F4/80, macrophage mannose receptor, E-selectin, intercellular adhesion molecule-1, phosphatidylserine, and matrix metalloproteinases. In addition, we discuss a new tool that is being introduced in the field, namely the use of nanobodies as tracers. Finally, we describe additional molecules displaying specific features in joint inflammation and propose these as potential new molecular imaging targets, more specifically receptor activator of nuclear factor κB and its ligand, chemokine receptors, vascular cell adhesion molecule-1, α_Vβ₃ integrin, P2X7 receptor, suppression of tumorigenicity 2, dendritic cell-specific transmembrane protein, and osteoclast-stimulatory transmembrane protein.     

Hand bone loss as an outcome measure in established rheumatoid arthritis: 2-year observational study comparing cortical and total bone loss

The aim of this 2-year longitudinal observational study was to explore hand bone loss as a disease outcome measure in established rheumatoid arthritis (RA).     

Quantitative assessment of synovitis in patients with rheumatoid arthritis using fluorescence optical imaging

Introduction

To prospectively evaluate quantitative assessment of fluorescence optical imaging (FOI) for differentiation of synovitic from non-synovitic joints in patients suffering from rheumatoid arthritis (RA).

Methods

FOI of the hands was performed in patients with active RA, and a stratified quantitative fluorescence readout (FLRO) of 3 phases (1-120 s; 121-240 s; 241-360 s) was generated for 5 individual joints of the clinical predominant hand (carpal joint, metacarpophalangeal and proximal interphalangeal joints of digits II & III). To dissect the effect of the overall perfusion of the hand from the perfusion due to synovitis, a fluorescence ratio (FLRA) was additionally calculated, dividing each FLRO by the readout of the eponychium of digit II. The mean FLRO and FLRA were compared between joints with absent vs. present synovitis determined by clinical examination, grayscale, color Doppler ultrasonography, or magnetic resonance imaging (MRI).

Results

The analysis for 90 individual joints from 18 patients yielded FLRO ranging from 4.4 to 49.0 × 10³, and FLRAs ranging from 0.37 to 2.27. Overall, the analyses based on the FLRA revealed a higher discrimination than the analyses related to the FLRO, demonstrating most significant differences in phases 2 and 3. A sensitivity of 26/39 (67%) and a specificity of 31/40 (77%) were calculated for FLRA of phase 3 using a cut-off value of more than 1.2 to detect MRI-confirmed synovitis with FOI.

Conclusions

FOI has a potential for visualizing synovitis in subjects with RA. For adequate FOI interpretation, quantitative analysis should be based on the novel FLRA calculated for phases 2 and 3.     

Risk factors for bone loss in patients with rheumatoid arthritis treated with biologic disease-modifying anti-rheumatic drugs

Objective

Osteoporosis is a complication of rheumatoid arthritis. We examined the risk factors for bone loss in rheumatoid arthritis patients receiving biological disease-modifying anti-rheumatic drugs. Lumbar spine and femoral neck bone mineral density was measured at two time points in 153 patients with rheumatoid arthritis managed with biological disease-modifying anti-rheumatic drugs. We examined patients’ variables to identify risk factors for least significant reduction of bone mineral density.

Results

Least significant reduction of lumbar spine bone mineral density (≤ ? 2.4%) was seen in 13.1% of patients. Least significant reduction of femoral neck bone mineral density (≤ ? 1.9%) was seen in 34.0% of patients. Multiple logistic regression analysis showed that a risk factor for least significant reduction of the lumbar spine was high-dose methylprednisolone use. Multiple regression analysis showed that a risk factor for least significant reduction of the femoral neck was short disease duration. Our findings showed that a risk factor for femoral neck bone mineral density reduction was a short disease duration. These findings suggest that rheumatoid arthritis patients receiving treatment with biological disease-modifying anti-rheumatic drugs may benefit from earlier osteoporosis treatments to prevent femoral neck bone loss.

     

Trabecular bone loss in collagen antibody-induced arthritis

IntroductionPostmenopausal women with rheumatoid arthritis (RA) have increased risk of developing osteoporosis due to chronic inflammation and estrogen deprivation. Collagen antibody-induced arthritis (CAIA), an experimental polyarthritis model representing the effector phase of arthritis, is mainly mediated by the innate immune system. Compared to the widely used collagen-induced arthritis model, CAIA is conveniently short and can be used in C57BL/6 mice, enabling studies with knock-out mice. However, the impact on bone of the CAIA model in C57BL/6 mice has not previously been studied. Therefore, the aim of this study was to determine if CAIA can be used to study postmenopausal arthritis-induced osteoporosis.MethodsCAIA was induced by administration of collagen-type II antibodies and lipopolysaccharide to ovariectomized female C57BL/6J mice. Control mice received lipopolysaccharide, but no antibodies. Nine days later, femurs were collected for high-resolution micro-CT and histomorphometry. Serum was used to assess cartilage breakdown and levels of complement. Frequencies of immune cell subsets from bone marrow and lymph nodes were analyzed by flow cytometery.ResultsTrabecular bone mass was decreased and associated with increased number of osteoclasts per bone surface in the CAIA model. Also, the frequency of interleukin-17⁺ cells in lymph nodes was increased in CAIA.ConclusionThe present study show that CAIA, a short reproducible arthritis model that is compatible with C57BL/6 mice, is associated with increased number of osteoclasts and trabecular bone loss.     

VEGF and imaging of vessels in rheumatoid arthritis

Angiogenesis is a prominent feature of rheumatoid synovitis. Formation of new blood vessels permits a supply of nutrients and oxygen to the augmented inflammatory cell mass and so contributes to perpetuation of joint disease. Vascular endothelial growth factor (VEGF) is a potent endothelial cell-specific growth factor that is upregulated by proinflammatory cytokines and by hypoxia. Serum VEGF concentrations are elevated in rheumatoid arthritis (RA) and correlate with disease activity. Furthermore, serum VEGF measured at first presentation in RA is highly significantly correlated with radiographic progression of disease over the subsequent year. Power Doppler ultrasonography is a sensitive method for demonstrating the presence of blood flow in small vessels and there is a very close relation between the presence or absence of vascular flow signal on power Doppler imaging and the rate of early synovial enhancement on dynamic gadolinium-enhanced magnetic resonance imaging (MRI) of joints with RA. Images obtained by both dynamic enhanced MRI and power Doppler ultrasonography correlate with vascularity of synovial tissue as assessed histologically. In early RA, there is a striking association between joint erosions assessed on high-resolution ultrasonography and vascular signal in power Doppler mode. Collectively, these findings implicate vascular pannus in the erosive phase of disease and strongly suggest that proangiogenic molecules such as VEGF are targets for novel therapies in RA. Animal model data supports this concept. It seems likely that serological and imaging measures of vascularity in RA will become useful tools in the assessment of disease activity and response to therapy.     

Quantitative analysis of cytokine gene expression in rheumatoid arthritis

Previous studies of the cytokine profile of rheumatoid arthritis (RA) have been primarily limited to the assessment of the levels of these mediators in synovial fluid (SF) or synovial tissues (ST) by biologic or immunologic assays. We have studied cytokine gene expression in RA by in situ hybridization of SF cells, enzymatically dispersed ST cells, and frozen sections of ST. RA ST cells (n = 7) were studied and a high percentage of cells hybridized to the following anti-sense probes: IL-6 = 19 +/- 3.3%; IL-1 beta = 9.9 +/- 1.7%; TNF-alpha = 5.8 +/- 1.4%; granulocyte-macrophage-CSF = 2.2 +/- 0.8%; transforming growth factor-beta 1 = 1.3 +/- 0.2% (p less than 0.05 for each compared to sense probes). Similar results were found using osteoarthritis ST cells, although the percentage of cells expressing the IL-6 gene (7.1 +/- 2.5%) was significantly less in osteoarthritis compared to RA. RA ST cells did not significantly bind the IFN-gamma probe (0.2 +/- 0.1% positive), although they were capable of expressing the IFN-gamma gene if stimulated with PHA. The OKM1+ population of ST cells (i.e., macrophage lineage cells) was greatly enriched for IL-1 beta and TNF-alpha, whereas the OKM1- population (lymphocytes, fibroblasts, and type B synoviocytes) was enriched for IL-6. The vast majority of cells expressing the IL-6 gene were non-T cells. Furthermore, hybridization to RA ST frozen sections localized IL-6 mRNA to the synovial lining layer, which is comprised of type A and type B synoviocytes. In contrast to the high level of cytokine gene expression observed in ST, SF cells did not hybridize significantly to any of the cytokine probes. If stimulated with LPS or PHA, SF cells expressed IL-1 beta or IFN-gamma genes, respectively.     

A combination of methotrexate and zoledronic acid prevents bone erosions and systemic bone mass loss in collagen induced arthritis

Introduction  

Osteoclasts play a key role in the pathogenesis of bone erosion and systemic bone mass loss during rheumatoid arthritis (RA). In this study, we aimed to determine the effect of methotrexate (MTX) and zoledronic acid (ZA), used alone or in combination, on osteoclast-mediated bone erosions and systemic bone mass loss in a rat model of collagen induced arthritis (CIA). We hypothesized that MTX and ZA could have an additive effect to prevent both bone erosion and systemic bone loss.     

The value of sensitive imaging modalities in rheumatoid arthritis

X-ray evaluation of rheumatoid joints is relatively inexpensive, is widely available and has standardised methods for interpretation. It also has limitations, including the inability to reliably determine structural change in less than 6-12 months, the need for experienced readers to interpret images and the limited acceptance of this technique in routine clinical practice. High-frequency ultrasound, with or without power Doppler, and magnetic resonance imaging of rheumatoid joints permit an increasingly refined analysis of anatomic detail. However, further research using these sensitive imaging technologies is required to delineate pathophysiological correlates of imaging abnormalities and to standardise methods for assessment.     

Mechanisms of bone loss in inflammatory arthritis: diagnosis and therapeutic implications

Rheumatoid arthritis represents an excellent model in which to gain insights into the local and systemic effects of joint inflammation on skeletal tissues. Three forms of bone disease have been described in rheumatoid arthritis. These include: focal bone loss affecting the immediate subchondral bone and bone at the joint margins; periarticular osteopenia adjacent to inflamed joints; and generalized osteoporosis involving the axial and appendicular skeleton. Although these three forms of bone loss have several features in common, careful histomorphometric and histopathological analysis of bone tissues from different skeletal sites, as well as the use of urinary and serum biochemical markers of bone remodeling, provide compelling evidence that different mechanisms are involved in their pathogenesis. An understanding of these distinct pathological forms of bone loss has relevance not only with respect to gaining insights into the different pathological mechanisms, but also for developing specific and effective strategies for preventing the different forms of bone loss in rheumatoid arthritis.     

Normal acquisition and loss of bone mass

The natural patterns of bone mass accumulation and loss with age represent the templates of individual life cycle periods that are distinguished by marked, physiologically and genetically identifiable, changes in bone mass. During the third trimester of pregnancy, maternal calcium absorption increases and the fetus accumulates about two-thirds of the total bone mass of the term infant. In early infancy, human milk calcium is derived primarily from maternal bone stores, which incur substantial bone losses that are quickly replenished during and after weaning. At puberty, a marked increase in bone mass occurs in conjunction with the initial physical and hormonal changes that characterize this stage. Calcium absorption and bone calcium deposition rates peak in females shortly before menarche. At that time, the bone calcium deposition rate is approximately five times that of adulthood. Skeletal bone mass reaches over 90% of its maximum by age 18 (earlier in females) but does not peak until age 25-30. At some point in mid-life, women experience perimenopause, the 3- to 5-year period prior to menopause during which estrogen levels begin to drop and there are marked increases in bone resorption and loss. Throughout adulthood, calcium absorption efficiency from the diet gradually declines.     

Mechanisms of bone loss in inflammatory arthritis: diagnosis and therapeutic implications

Rheumatoid arthritis represents an excellent model in which to gain insights into the local and systemic effects of joint inflammation on skeletal tissues. Three forms of bone disease have been described in rheumatoid arthritis. These include: focal bone loss affecting the immediate subchondral bone and bone at the joint margins; periarticular osteopenia adjacent to inflamed joints; and generalized osteoporosis involving the axial and appendicular skeleton. Although these three forms of bone loss have several features in common, careful histomorphometric and histopathological analysis of bone tissues from different skeletal sites, as well as the use of urinary and serum biochemical markers of bone remodeling, provide compelling evidence that different mechanisms are involved in their pathogenesis. An understanding of these distinct pathological forms of bone loss has relevance not only with respect to gaining insights into the different pathological mechanisms, but also for developing specific and effective strategies for preventing the different forms of bone loss in rheumatoid arthritis.     

Detection of bone erosions in rheumatoid arthritis wrist joints with magnetic resonance imaging, computed tomography and radiography

Background

The objectives of the present study were, with multidetector computed tomography (CT) as the reference method, to determine the performance of magnetic resonance imaging (MRI) and radiography for the detection of bone erosions in rheumatoid arthritis wrist bones, and to test whether measuring volumes of erosions on CT and MRI is reproducible and correlated to semiquantitative assessments (scores) of erosions on CT, MRI and radiography.

Methods

Seventeen patients with rheumatoid arthritis and four healthy control individuals underwent CT, MRI and radiography of one wrist, performed on the same day. CT was performed on a Philips Mx8000IDT unit (voxel size 0.4 mm × 0.4 mm × 1 mm) and MRI was performed on a Philips Panorama 0.6T unit (voxel size 0.4 mm × 0.4 mm × 0.4 mm). Images were evaluated separately for erosions in all wrist bones and were scored according to the principles of the Outcome Measures in Rheumatology Rheumatoid Arthritis MRI Scoring System (CT and MRI) and the Sharp/van der Heijde (radiographs) scoring methods. Measurements of erosion volumes of all erosions were performed twice with a 1-week interval.

Results

With CT as the reference method, the overall sensitivity, specificity and accuracy (concordance) of MRI for detecting erosions were 61%, 93% and 77%, respectively, while the respective values were 24%, 99% and 63% for radiography. The intramodality agreements when measuring erosion volumes were high for both CT and MRI (Spearman correlation coefficients 0.92 and 0.90 (both P < 0.01), respectively). Correlations between volumes and scores of individual erosions were 0.96 for CT and 0.99 for MRI, while they were 0.83 (CT) and 0.80 (MRI) for persons' total erosion volume and total score (all P < 0.01).

Conclusion

With CT as the reference method, MRI showed moderate sensitivity and good specificity and accuracy for detection of erosions in rheumatoid arthritis and healthy wrist bones, while radiography showed very low sensitivity. The tested volumetric method was highly reproducible and correlated to scores of erosions.