The results from this study provide evidence that hand DEXA is a more sensitive outcome measure than radiographic joint damage scores, particularly for bone damage in early RA. At 24 weeks, mean hand BMD was reduced by 2.5%, and on the individual level approximately half (47%) of the patients had lost hand BMD exceeding the measurement error. In the subgroup of 58 patients with both hand radiographs and DEXA, on the individual level only 22% of the RA patients had deteriorated in modified Sharp score after 48 weeks whereas 50% had already lost significant hand BMD after 24 weeks. This makes hand DEXA a highly sensitive tool to detect bone damage, especially in the early stage of the disease, a crucial time for assessing new treatments.
Although bone loss in RA occurs both as periarticular (eg assessed at hand) and generalised osteoporosis (eg assessed in the spine or hip), measures of periarticular osteoporosis are more suitable for assessment of bone damage than measures of generalised osteoporosis, for several reasons. Bone loss in early RA occurs more rapidly in the hand than the hip and spine.8
Furthermore, the rate of hand bone loss, as shown in our study, is higher than that in the spine and hip, and the precision of DEXA is also superior at the hand compared with the hip and spine (table 3). By applying our precision data, the advantage of hand DEXA using mean values of both hands compared with hip and spine becomes obvious: in the hands, a bone loss of only 2.3% is required to identify patients with individual bone loss, whereas in the femoral neck and lumbar spine, bone losses as high as 7.8% and 6.6%, respectively, are required.
Theoretically, the best site to measure periarticular bone loss in RA would be around the finger joints, particularly the metacarpophalangeal (MCP) joints and proximal interphalangeal (PIP) joints. Our choice to use DEXA of the whole hand instead of the finger joints to assess periarticular bone loss in patients with RA was based on the literature and our own reproducibility tests comparing the two principal measurement strategies. DEXA of the whole hand compared with local measures around single joints is more feasible,20
has better precision20
and also reflects the whole inflammatory disease process taking place in all affected joints in the hands. In the study by Alenfeld et al
, precision (CV) for DEXA of the whole hand was 0.9%, but for periarticular regions at the MCP joints of the second to fifth fingers, precision was poorer, ranging from 2.7% to 3.2%.20
In our own analyses, we also found poorer precision for DEXA measurements around finger joints compared with whole hand measurements. Furthermore, no differences were found for percentage bone loss between DEXA measurements in the finger joints and whole hand (unpublished data).
In contrast to DEXA, the reproducibility for x
ray scoring methods may be more dependent on the reader and on the study population. For radiographic scoring systems, it has been shown that x
rays even of early RA are scored with great variability, even when scoring is performed by the same reader.21
In the study by Lassere et al
, assessing reproducibility for the Sharp–van der Heijde method (range 0 to 448), SDD ranged from 4.7 to 15.5 units and was dependent on the source population used for SDD calculation, patient disease activity and the readers.19
Direct comparison of the measurement error of the two methods in our study is restricted by several limitations. There is a difference in how the duplicate measures are obtained for the SDC calculation for the two methods. Calculation of the DEXA SDC/SDD is recommended to be based on duplicate measures of scans performed on the same day or some days apart,13,14
which is a point estimate of the measurement error. For radiographic scoring methods including the Sharp–van der Heijde method, the SDC calculation for practical purposes is based on readings from baseline and follow‐up films in each individual, and it is recommended they be read in a paired chronological order by two assessors. Thus, the SDC for DEXA is based on intra‐reader reproducibility, whereas the SDC for the radiographic measurements is based on inter‐reader reliability. However, this difference in the methods used to assess agreement reflects the intrinsic difference in the practical measurement methods between DEXA and radiographic scoring. Thus, the increased sensitivity of DEXA is a product of the precision of the method. The face validity of the hand DEXA method also needs to be addressed. The fact that the patients were enriched for features predicting more radiographic damage means that differences between DEXA and radiographic damage were, if anything, underestimated.
Although erosions are pathognomonic for bone damage in RA, bone loss over time is also seen in healthy people, especially in postmenopausal women. However, for short study periods, this does not seem to be a significant problem. In our healthy controls used for assessing the precision of hand DEXA, no bone loss was seen in the hand when the duplicate measurements performed 3 months apart were compared. Joint destruction is also more directly related to patient physical function and health status than is osteoporosis, as bone loss in itself is a symptom‐free feature leading to no structural changes on the joint surface.5,22
Radiographic joint damage using the Sharp score (scoring both erosions and joint‐space narrowing) has been shown to increase linearly over time.5
In contrast, the rate of hand bone loss measured by DEXA has been shown to decrease after the first 2–3 years of disease duration,7,23
which makes DEXA of the hands less usable in the later and established stages of the disease. However, the same pattern is also found for the Larsen score, which only scores erosions.24
In a 10 year follow‐up study of early RA (disease duration<12 months). Linqvist et al
showed that radiographic progression using the Larsen score was most rapid during the first 2 years, and that 75% of all damage occurred during the first 5 years of disease.24
In comparison with DEXA, other modern imaging modalities, such as MRI25,26
are not suitable for assessment of bone mass. They are superior to radiographs in detecting erosions at an early stage of the disease and assessing soft‐tissue abnormalities and synovitis; however, they are currently often not as widely available as DEXA, and there is a lack of standardisation for general clinical use in early RA.
To be a clinically relevant outcome measure in early RA, and eventually an alternative to radiographic scoring methods in the early stage of the disease, bone loss should be a direct consequence of the inflammatory disease process and be related to joint erosions. Substantial data from both animal and clinical studies support the theory that the osteoclast cells play a pivotal role in the development of both osteoporosis and erosions in RA. This common cellular mechanism may be explained by activation of the receptor activator of nuclear factor kB ligand (RANKL), which is a key factor in the activation and differentiation of osteoclasts by binding to its receptor RANK on premature osteoclasts.28,29
Tumour necrosis factor (TNF)‐α and interleukin‐1, which play a pivotal role in the pathogenesis of synovitis in RA, have been found to be regulators of osteoclastic bone resorbtion by upregulating RANK.30,31
Studies in human TNF‐transgenic (hTNFtg) mice have shown an increase in both joint destruction and generalised bone loss compared with wild‐type mice.28,32
The concept of osteoclast inhibition has recently been confirmed in humans.33
In the present study, only patients with RA with poor prognosis were included. Thus, the results are of limited value understanding bone loss in patients with less poor prognostic disease. Further studies in different patient cohorts are therefore warranted to examine the generalisability of the method.