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. 2010 Apr;2(2):79–87. doi: 10.1177/1759720X10362297

Using Hand Bone Mass Measurements to Assess Progression of Rheumatoid Arthritis

Mari Hoff 2, Glenn Haugeberg 1
PMCID: PMC3383477  PMID: 22870439

Abstract

In rheumatoid arthritis (RA) bone involvement presents as joint erosions in addition to generalized and periarticular osteoporosis. Joint erosions on radiographs of the hands and feet are considered to be the gold standard to evaluate progression of bone and joint damage in RA, even though erosions on radiographs are not used as a marker of early bone involvement. Periarticular bone loss seen on radiographs may be the first sign of bone involvement in RA. Over the last decade there has been an increased awareness of the importance of early aggressive treatment in RA, leading to a need for methods which can identify bone involvement in the early stages of RA. As inflammatory bone loss, especially at the hand, has been shown to occur early in RA, quantitative measures of hand bone loss have been proposed as an outcome measure for the detection of bone involvement. In this review article we present data supporting the hypothesis that both erosions and osteoporosis in RA occur as a result of the same pathophysiological mechanisms activating the osteoclast. Furthermore the role of hand bone loss as an early marker of inflammatory bone involvement, a predictor of subsequent radiographic joint damage and a response variable to anti-inflammatory treatment is discussed.

Keywords: erosions, osteoporosis, rheumatoid arthritis

Introduction

Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disease characterized by synovitis and destruction of cartilage and bone in joints, especially the small joints of the hands and feet [Klareskog et al., 2009; Feldmann et al., 1996]. The prevalence of RA is about 0.5–1.0% [Alamanos et al., 2006; Kvien et al., 1997] with an annual incidence of 25–50/100,000 [Alamanos et al., 2006; Uhlig et al., 1998]. This makes RA one of the most frequent inflammatory rheumatic diseases. The impact of the disease is significant for both the individual and society as a whole, as the disease is accompanied by increased morbidity, disability and even mortality [Young and Koduri, 2007].

While disability in early RA is driven by inflammation, destruction of bone is the main reason for disability in established RA [Klareskog et al., 2009; Smolen et al., 2007; van der Heijde, 2001]. Prevention of bone damage in RA is thus of major importance in avoiding future disability. Bone involvement in RA presents as erosions, generalized osteoporosis and periarticular (juxtaarticular) osteoporosis [Sambrook, 2000]. The prevalence of generalized osteoporosis has been found to be doubled in RA patients compared with the normal population [Haugeberg et al., 2000b], and both hip and vertebral fractures occur more frequently in RA patients than in the normal population [van Staa et al., 2006; Orstavik et al., 2004a, 2004b; Huusko et al., 2001]. In the 1987 American College of Rheumatology (ACR) revised criteria of RA, both erosions and periarticular osteoporosis are defined as typical hallmarks of bone involvement in RA [Arnett et al., 1988]. To date, conventional radiographs have been considered to be the gold standard to evaluate the progression of bone and joint damage in RA [Boini and Guillemin, 2001; van der Heijde, 1996]. However, erosions may not appear on radiographs early in the disease and periarticular osteoporosis may occur before the erosions are visible [Brook and Corbett, 1977; Bywaters, 1960]. Periarticular osteoporosis cannot be quantified based on the visual impression seen on radiographs and has to be detected by quantitative bone mass measures [Bottcher et al., 2006c; Jergas et al., 1994].

In this article we review the mechanism for bone involvement in RA, methods for quantitative assessment of hand bone density and discuss the ability of quantitative hand bone measures to capture bone involvement and the progression of bone damage in RA.

Mechanism for bone involvement in rheumatoid arthritis

Results from animal and human studies support the hypothesis that both erosions and osteoporosis in RA are results of the same inflammatory patho-physiological mechanism involving the osteoclast [Cohen et al., 2008; Jarrett et al., 2006; Goldring and Gravallese, 2004; Herrak et al., 2004; Sims et al., 2004; Redlich et al., 2002; Gravallese et al., 1998]. The important role of the osteoclast was demonstrated in an animal study where trans-genic mice that expressed human tumour necrosis factor (TNF)-α and developed a severe destructive arthritis were crossed with mice lacking osteo-clasts. The resulting mutant mice developed arthritis, but were fully protected against bone destruction [Redlich et al., 2002]. Further, suppression of the osteoclast by the potent bisphosphonate zoledronic acid has indicated a reduction of erosions both in animal studies [Goldring and Gravallese, 2004; Herrak et al., 2004; Sims et al., 2004] and in human studies [Jarrett et al., 2006].

The activation and development of osteoclasts depends on stimulation from receptor activator of nuclear factor-K ligand (RANKL). RANKL is a member of the TNF ligand superfamily of cytokines and binds to the receptor activator of nuclear factor-K (RANK) [Gravallese, 2002]. The interaction of this receptor—ligand pair is essential for osteoclastogenesis [Schett et al., 2005]. Mice with a serum transfer model of arthritis that were lacking RANKL were protected against bone destruction [Pettit et al., 2001]. Osteoprotegerin (OPG) is a naturally occurring decoy receptor for RANKL. The ratio of RANKL/OPG determines the degree of osteoclastmediated bone resorption [Gravallese, 2002; Green and Deodhar, 2001]. A new antibody against RANKL, denosumab, has been found to reduce the development of erosions in RA, but had no influence on the disease activity [Cohen et al., 2008].

The expression of RANKL is stimulated by pro-inflammatory cytokines such as TNF-α, interleukin-1 (IL-1), IL-6, IL-16, IL-17 and macrophage colony-stimulating factor (M-CSF) [Gravallese, 2002; Green and Deodhar, 2001]. It has also been suggested that TNF-α may have the ability to bind directly to osteoclast precursors through TNF-α receptor and stimulate the osteoclast formation [Schett, 2007; Lam et al., 2000]. This dual effect of TNF-α on the osteoclast may explain why treatment with anti-TNF therapy reduces hand bone loss and erosions independently of disease activity, in contrast to metho-trexate [Hoff et al., 2009d; Emery et al., 2009; Smolen et al., 2009].

Recently, interest has grown in the osteoblast in inflammatory arthritis. An increased bone resorption should normally be coupled to an increased bone formation by the osteoblast, but this is not the case in RA. Studies suggest that the inflammation may suppress the bone formation activity of the osteoblast. The osteoblast is activated by the Wnt (wingless protein) pathway which also leads to an induction of OPG and thus reduces the activity of the osteoclast [Schett, 2009; Schett et al., 2008]. TNF-α seems to induce Dickkopf 1 (DKK1) which inhibits Wnt. This further leads to a down-regulation of both the osteoblast and OPG, resulting in an inhibition of the bone formation. In this manner RA inflammation also seems to inhibit the osteoblast, which gives an additive negative effect of inflammation on bone [Garnero et al., 2008; Schett et al., 2008].

Measurements of bone density

As mentioned in the introduction, hand bone loss cannot be quantified or graded sufficiently on radiographs. It is estimated that bone loss less than 20–40% cannot be detected on plain radiographs [Bottcher et al., 2006c; Jergas et al., 1994]. Several devices have been developed for quantitative assessments of bone density [Njeh and Genant, 2000], e. g. quantitative ultrasound (US) [Njeh et al., 1997], quantitative computer tomography (qCT) [Cann, 1988], dual energy X-ray absorptiometry (DXA) [Blake and Fogelman, 1997] and radiogrammetry [Rosholm et al., 2001]. Owing to their feasibility and precision, DXA and digital X-ray radiogrammetry (DXR) are the two methods most frequently used to study inflammatory osteoporosis in RA (Table 1).

Table 1.

Selected studies on hand bone loss in patients with rheumatoid arthritis (numbers of participants in parenthesis).

Study Diagnosis Disease duration DXR-BMD % change DXR-MCI % change DXA-BMC % change DXA-BMD % change
Daragon et al. [2001] RA (15)/ORD (15) < 0.5 yr 1 yr: −2.2/−0.3 1 yr: −2.6/−0.4
Deodhar et al. [2003] RA (29) < 2 yr 1 yr: −5.5
2 yr: −7.5
3 yr: −9.8
5 yr: −10.0
Jensen et al. [2004]* RA (51)/ORD (21) 2 yr 2 yr: −5.0/−2.0 2 yr: NS
Stewart et al. [2004] RA (24) Erosive/non-erosive <1 yr 1 yr: −7.1/−0.2 1 yr: −8.1–1.0 yr:−5.4−1.0
Haugeberg et al. [2005] RA (95) Prednisolone users/non-users <2 yr 2 yr: −3.6/−7.1
Bottcher et al. [2005b] RA (258) <1 yr 1 yr: −10.7 1 yr: −14.3
6 yr: −32.1 6 yr: −33.3
Haugeberg et al. [2006] RA (13)/ORD (19)/arthralgia (42) <1 yr 1 yr: −4.3/−0.5/−0.9
Hoff et al. [2007]* RA (215) 9 yr 2 yr: −0.9 2 yr: −1.2 2 yr:0.0
Hoff et al. [2009a]* RA (136) <4 yr 1 yr: −1.7
Gütler-Yuksel et al. [2009] RA (218) <2 yr 1 yr: −1.4
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*

Median change, otherwise mean change.

DXR, digital X-ray radiogrammetry; BMD, bone mineral density; MCI, metacarpal cortical index; DXA, dual energy X-ray absorptiometry; BMC, bone mineral content; yr, years; RA, rheumatoid arthritis; ORD, other rheumatic disease; NS, nonsignificant.

DXA is considered as the gold standard for the detection and management of osteoporosis [Kanis et al., 2008]. The method is based on the known differences in the relative attenuation of high-energy and low-energy X-rays by bone and soft tissue [Blake and Fogelman, 1997]. Software to measure hand DXA is now commercially available. Both bone mineral density (BMD) and bone mineral content (BMC) can be measured, but BMD has been preferred due to better precision [Murphy et al., 2008; Daragon et al., 2001]. DXA-BMD can be calculated from both the whole hand and regions of interest around the joints [Alenfeld et al., 2000; Deodhar et al., 1994]. Even though measures of bone loss around the joints shows larger values of bone loss, the method for measuring the whole hand is more feasible and the precision is considerably better than for regions around finger joints [Murphy et al., 2008; Daragon et al., 2001; Alenfeld et al., 2000].

DXR is a computer version of the traditional technique of radiogrammetry [Barnett and Nordin, 1960] and measures cortical BMD from defined regions of interest in the second, third and fourth metacarpal bone. The final BMD estimate is defined as:

DXR-BMD=c×VPAcomb×(1−p)

[Rosholm et al., 2001; Jorgensen et al., 2000], where c is a density constant, VPA is volume per area and p is porosity. Porosity is defined as the percentage of cavities not occupied by mineral matter and is usually in the range of 2–4%. The DXR method also measures DXR-metacarpal cortical index (MCI), defined as the combined cortical thickness divided by the bone width. DXR-MCI is a relative bone measure and less dependent on bone size and bone length than DXR-BMD [Hyldstrup and Nielsen, 2001; Nielsen, 2001]. DXR can be analysed both from conventional X-rays [Bottcher et al., 2004; Rosholm et al., 2001] or from digitized X-rays by the dxr-online system (Sectra, Linkoping) [Guler-Yuksel et al., 2009].

A limitation of the DXR method is that BMD or MCI cannot be measured in patients with severe deformities, as the system does not recognize the regions of interest in the metacarpal bones. Further, the method does not allow DXR to be measured in patients with metal implants in hands. These limitations of DXR exclude analysis of patients with severe disease.

The precision has been shown to be good for both the DXA and the DXR method. The in-vivo short-term precision expressed as coefficient of variance (CV%) for hand DXA-BMD has been calculated to be 0.8–1.4% for the whole hand [Haugeberg et al., 2007; Berglin et al., 2003; Daragon et al., 2001; Alenfeld et al., 2000] and 0.9–4.5% for regions around the joints [Murphy et al., 2008; Harrison et al., 2002; Daragon et al., 2001; Alenfeld et al., 2000]. For DXR-BMD using conventional radiographs the CV has been found to be 0.28–0.46% and for DXR using digitized radiographs (dxr-online) 0.14–0.30% [Hoff et al., 2009b]

Periarticular versus generalized osteoporosis

The small joints in hands and feet are the most frequently involved joints in the inflammatory disease process in RA [Arnett et al., 1988]. Thus, bone density measures of the hand are recommended for assessment of periarticular osteoporosis in RA whereas bone density measures at, for example, the spine and hip are used as measurement sites for generalized osteoporosis.

Studies support that hand bone loss measured by DXA and DXR takes place in early RA [Haugeberg et al., 2006; Jensen et al., 2004; Deodhar et al., 2003], even in the undifferentiated stage of the RA disease process [Haugeberg et al., 2006; Jensen et al., 2004]. Patients with RA have significantly lower hand DXA-BMD compared with healthy controls [Alenfeld et al., 2000] and patients suffering from psoriatic arthritis [Harrison et al., 2002]. In longitudinal studies, RA patients have been found to lose more hand BMD compared both with patients with other rheumatic diseases [Haugeberg et al., 2006; Jensen et al., 2004; Daragon et al., 2001] and with healthy controls [Deodhar et al., 1995].

Studies also indicate that hand bone loss in early RA occurs more rapidly than bone loss at the hip and spine [Guler-Yuksel et al., 2009; Haugeberg et al., 2006; Devlin et al., 1996]. Radiographic joint damage has been shown to be more strongly correlated with low hand DXR-BMD than DXA-BMD at the hip and spine [Bottcher et al., 2004; Haugeberg et al., 2004]. These studies suggest that whereas the prolonged course of RA, including immobility and the use of corticos-teroids, may be more associated with generalized bone loss [Haugeberg et al., 2000a], the effect of inflammation may have a greater impact on hand bone loss [Haugeberg et al., 2006].

Predictors of hand bone loss and the association with inflammation

The associations between disease factors and hand bone loss in RA has been studied [Boyesen et al., 2009; Guler-Yuksel et al, 2009; Hoff et al., 2007, 2009a, 2009e; Haugeberg et al., 2006; Deodhar et al., 1995, 2003]. Hand bone loss both detected by DXA (BMC and BMD) and DXR (BMD and MCI) has been found to be correlated with high baseline C-reactive protein (CRP) and DAS 28 [Guler-Yuksel et al., 2009; Hoff et al., 2007, 2009a, 2009e; Haugeberg et al., 2006; Deodhar et al., 1995]. Patients with positive rheumatoid factor (RF) or antibodies against cyclic citrullinated protein (anti-CCP) have also been found to be at a higher risk of losing hand bone [Boyesen et al., 2009; Haugeberg et al., 2006; Deodhar et al., 1995].

Studies suggest that DXA-BMD loss takes place only in patients with short disease duration while DXR-BMD loss can be detected during the whole disease process [Hoff et al., 2007, 2009a; Deodhar et al., 1995, 2003]. Degenerative bone changes and increased inflammation in the small joints of the hand in the first years of the disease have been suggested to partially explain this finding [Deodhar et al., 1994]. As DXA measures both trabecular and cortical bone a third explanation could be that the rate of trabecular and cortical bone loss is different in early versus late stages of the disease. The fact that the two methods for bone measurements are based on completely different techniques and that the precision of the DXR method [Hoff et al., 2008, 2009b; Jorgensen et al., 2000] is better than the DXA method [Haugeberg et al., 2007; Daragon et al., 2001; Alenfeld et al., 2000] may also contribute to the explanation. In the few previous studies which have compared hand DXR and DXA in early RA disease the authors have suggested that changes in DXR are more sensitive than DXA to disease activity [Hoff et al., 2007; Jensen et al., 2004, 2005].

Cross-sectional studies have also demonstrated that hand BMD is lower in RA patients with high disease activity both for DXR [Bottcher et al., 2005a] and DXA [Devlin et al., 1996].

Hand bone loss as response measure to treatment

Suppressing the inflammation by anti-TNF therapy has significantly reduced the progression of radiographic joint damage in RA patients compared with conventional disease-modifying antirheumatic drugs (DMARDs) treatment, e. g. methotrexate [van der Heijde et al., 2006; Breedveld et al., 2006; Keystone et al., 2004; Klareskog et al., 2004; St Clair et al., 2004; Lipsky et al., 2000]. The hypothesis that erosions and hand bone loss are caused by the same mechanism suggest that anti-inflammatory treatment should have an effect on osteoporosis as well. Two studies have suggested that anti-TNF therapy did not have a significant effect on hand bone loss, but did reduce the bone loss in the hip [Haugeberg et al., 2009; Vis et al., 2006] and spine [Vis et al., 2006]. However, other studies involving more patients showed that patients treated with potent anti-inflammatory treatment such as prednisolone or anti-TNF therapy lost significantly less cortical bone as assessed by DXR compared with treatment with placebo or conventional DMARDs [Hoff et al., 2009e; Guler-Yuksel et al., 2009; Haugeberg et al., 2005]. The fact that patients using prednisolone had a lower rate of cortical hand bone loss than patients using placebo suggest that the potent anti-inflammatory effect of prednisolone exceeded its negative effect on bone in RA patients [Guler-Yuksel et al., 2009; Haugeberg et al., 2005].

The hypothesis of a common cellular mechanism of erosions and periarticular osteoporosis by the osteoclast is further supported by the observation from two treatment studies where the order of hand bone loss and radiographic progression in RA was similar across the different treatment arms [Hoff et al., 2009c; Guler-Yuksel et al., 2009]. Recent results from a study of the RANKL inhibitor denosumab further support the important role of the osteoclast, since this drug inhibited erosions and hand DXA-BMD loss, but not cartilage destruction or inflammation [Cohen et al., 2008; Deodhar et al., 2008]. In addition, anti-TNF therapy has been found to decrease hand bone loss independent of disease activity, supporting the hypothesis that TNF has a direct influence on the osteoclast [Hoff et al., 2009d].

Hand bone loss and radiographic damage

Despite the fact that periarticular osteoporosis and erosions are known as radiographic hallmarks of RA [Arnett et al., 1988], there is a lack of data on the relationship between hand bone loss and radiographic damage. Studies with conventional radiographs have in early studies supported the idea that bone loss precedes the development of erosions [Brook and Corbett, 1977; Bywaters, 1960]. Two cross-sectional studies have revealed a significant correlation (r) of 0.24–0.69 between DXA-BMD and radiographic damage [Ardicoglu et al., 2001; Deodhar et al., 1994], whereas no correlation was seen in a third study [Harrison et al., 2002]. Four longitudinal studies have been performed examining radiographic changes and DXA changes. Two studies revealed no significant correlation [Deodhar et al., 2003; Daragon et al., 2001], while in a 2-year longitudinal study including 43 patients a significant correlation (r = −0. 55) was found [Berglin et al., 2003]. The fourth study reported that the number of RA patients with early disease losing hand DXA-BMD, defined by the smallest detectable change (SDC) at 24 weeks, was significantly higher than the number of patients with a significant increase in radiographic damage detected by the van der Heijde (vdH) Sharp score at 48 weeks [Haugeberg et al., 2007]. The authors concluded that DXA-BMD was a more sensible method to detect bone damage in patients with early RA than conventional hand radiographic scores.

For the DXR-method, several cross-sectional studies have found DXR-BMD to be lower in patients with high radiographic joint damage scores than in patients with a low radiographic damage score [Jawaid et al., 2006; Bottcher et al., 2004, 2005a, 2005b, 2006a, 2006b, 2006c; Haugeberg et al., 2004]. In all these studies the correlation coefficient (r) between radio-graphic damage and DXR-BMD ranged from −0.42 to −0.66. Two longitudinal studies have examined the value of hand bone loss as a predictor of radiographic damage. One longitudinal pilot study including 24 patients indicated that DXR-BMD loss in the first year of follow-up in early RA (< 1 year disease duration at inclusion) could predict the new development of erosions at 4-year follow-up [Stewart et al., 2004]. Another study including 136 patients confirmed the predictive value of DXR-BMD. In this study DXR-BMD loss in the first year of follow up was an independent predictor for subsequent radiographic damage at 5 and 10 years, even when adjusted for other known predictors of radiographic progression such as baseline radio-graphic damage, anti-CCP and markers of inflammation [Hoff et al., 2009c].

Conclusion

Quantitative hand bone measurements performed by DXA and DXR have both shown promise as tools to detect early inflammatory bone involvement in RA. Hand bone loss is associated with markers of disease activity [e. g. CRP, erythrocyte sedimentation rate (ESR)] and disease severity (anti-CCP). Furthermore, the magnitude of hand bone loss in RA patients has been found to be greater than in patients with other inflammatory joint disorders, e. g. psoriatic arthritis. Finally, early hand bone loss is a predictor of subsequent radiographic damage, independent of other predictors for radiographic damage, e. g. anti-CCP and the presence of erosions. Despite the promising results of quantitative bone measures reported in the literature, there is still a need for further studies validating these methods before they may be used routinely in daily clinical care as outcome measures.

Footnotes

None declared

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