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The Skeleton in Rheumatoid Arthritis: Common Mechanisms for Bone Erosion and Osteoporosis?The effects of rheumatoid arthritis (RA) on bone have generally been considered as being manifest in 3 different ways: first, as juxtaarticular osteoporosis, second, as generalized osteoporosis, and third, as discrete bone erosion of individual joints. The pathophysiologic mechanisms of these 3 types of bone involvement have largely been thought to be separate. Thus bone erosions were originally considered to be due to direct invasion by synovial pannus. Juxtaarticular bone loss was thought to predominantly reflect the effect of local production of large amounts of bone resorbing cytokines. Generalized osteoporosis was considered multifactorial, with major contributions from progressive loss of mobility and/or corticosteroids1,2. More recent studies are challenging these concepts. For example, studies in human and experimental arthritis suggest that both juxtaarticular osteoporosis and bony erosions are mediated by the cellular action of osteoclasts3,4. Several cytokines [e.g., tumor necrosis factor-a (TNF) and interleukin 17] produced by synovium in RA promote osteoclast recruitment, and recent interest has focused on the involvement of receptor activator of nuclear factor kB ligand (RANKL, also known as osteoclast differentiating factor, ODF). RANKL/ODF is a transmembrane protein belonging to the TNF ligand superfamily. RANK-L or ODF is expressed by infiltrating T cells and synovial fibroblasts in RA and appears responsible for mediating osteoclast differentiation and activation at sites of bone erosion. Osteoclast precursors have been identified adjacent to areas of pannus invasion and erosion in RA3. In this issue, Sinigaglia, et al5 provide important new insights into the mechanisms of osteoporosis in RA and the relationship between bone loss, disease activity, and erosions. This study, although cross sectional, has the advantage of a very large sample size, with bone density measurements performed in 925 mainly postmenopausal women with RA. Of particular interest, the presence of erosions was associated with a higher prevalence of osteoporosis at both the spine and hip, suggesting that some of the disease mechanisms for generalized osteoporosis are common to those for local bone involvement. The central role of the osteoclast in these processes has also been suggested by other studies6. Sinigaglia reported the overall prevalence of osteoporosis, defined as a T score below -2.5, was 29% at the lumbar spine and 36% at the femoral neck. In interpreting these results it is important to appreciate that the T score is age dependent and 73% of their subjects were postmenopausal (mean age 57.4 yrs). Indeed, in otherwise healthy postmenopausal women, 22.5% of those between the age of 50 to 59 and 54% between age 60 to 69 years have been reported as osteoporotic at at least one site7. Thus it is not surprising that Sinigaglia also found the patients with a T score below -2.5 were significantly older than those above -2.5. In addition to age, other predictors of bone density included body mass index, Health Assessment Questionnaire (HAQ) score, and corticosteroid use. Vertebral fracture prevalence was less than the prevalence of nonvertebral fragility fractures (11% vs 15.2%) and surprisingly low, given that the study population were largely postmenopausal women using corticosteroids, but consistent with other studies8. The clinical effect of low dose corticosteroids on osteoporosis risk in Sinigaglia's study is difficult to assess. The authors concluded that the use of corticosteroids was associated with a 50% increase in the prevalence of osteoporosis using the T score threshold of -2.5. Thus the prevalence was 33% at the lumbar spine in users versus 21% in nonusers, but this fails to tell the whole story given that the corticosteroid users were again significantly older as well as having longer disease duration, higher HAQ scores, and more erosions. To accurately assess the effect of corticosteroids on bone mineral density (BMD) it is necessary to correct for age and disease effects. When the authors corrected for age effects by expressing BMD as Z scores rather than T scores, the effect of corticosteroid use on BMD was only a 0.3 reduction in Z score, a statistically significant but clinically relatively small effect. Moreover, although the median daily dose of prednisone was 5 mg, it ranged from 1 to 30 mg per day. The effect of corticosteroids on BMD after correcting for disease by multivariate analysis was even more intriguing. Predictors of osteoporosis in at least one site (spine or hip) included menopause status, use of corticosteroids, and HAQ score with odds ratios of 1.9, 1.5, and 1.3, respectively. Even more interesting were the multivariate models for vertebral fracture risk. HAQ and cumulative corticosteroid use remained significant, with odds ratios of 1.7 and 1.03, respectively. In other words, the risk of vertebral fracture was increased by 70% for a one unit increase in HAQ, but only by 3% for an extra gram of cumulative prednisone. Thus, although this study showed an adverse effect of corticosteroids on bone mass in RA, it is also consistent with the need to trade off these effects against improved disease control, as suggested by Gough, et al2 in longitudinal studies where bone loss was associated with disease activity measures such as C-reactive protein and HAQ score. In these circumstances any adverse effect of corticosteroids on bone may be outweighed by improved disease control leading to less disease related bone loss. These findings provide further compelling evidence for early control of synovitis and measures to maintain mobility in RA. In postmenopausal women, estrogen therapy would clearly seem appropriate, given its bone preserving and mild disease suppressing effects9. Although osteoclasts play a central role in all types of bone loss in RA, clinical studies to date suggest that disease suppression generally, rather than anti-osteoclastic therapy such as with bisphosphonates, is more effective in preventing bone loss. For example, the bisphosphonate pamidronate has been shown to suppress markers of bone resorption and improve bone density without influencing radiological progression in RA10,11. However, new therapeutic strategies such as OPG (osteoprotogerin), a soluble decoy receptor for ODF, show promise in phase I/II trials in postmenopausal osteoporosis12 and are likely to be of increasing importance for the interface of osteoporosis and inflammatory arthritis in the future.
PHILIP N. SAMBROOK, Address reprint requests to Dr. Sambrook.
REFERENCES 1.Sambrook PN, Eisman JA, Champion GD, Pocock NA, Eberl S, Yeates MG. Determinants of axial bone loss in rheumatoid arthritis. Arthritis Rheum 1987;30:721-8. 2.Gough AKS, Lilley J, Eyre S, Holder RL, Emery P. Generalised bone loss in patients with early rheumatoid arthritis occurs early and relates to disease activity. Lancet 1994;344:23-7. 3.Gravellese EM, Manning C, Tsay A, et al. Synovial tissue in rheumatoid arthritis is a source of osteoclast differentiation factor. Arthritis Rheum 2000;43:250-7. 4.Takayanagi H, Iizuka H, Juji T, et al. Involvement of receptor activator of nuclear factor KB ligand/osteoclast differentiation factor in osteoclastogenesis from synoviocytes in rheumatoid arthritis. Arthritis Rheum 2000;43:259-69.
5.Sinigaglia L, Nervetti A, Mela Q, et al. A multicenter cross-sectional study on bone mineral density in rheumatoid arthritis. 6.Gough A, Sambrook PN, Devlin J, et al. Osteoclastic activation is the principal mechanism leading to secondary osteoporosis in rheumatoid arthritis. J Rheumatol 1998;25:1282-9. 7.Arlot ME, Sornay-Rendu E, Garnero P, Vey-Marty B, Delmas P. Apparent pre- and postmenopausal bone loss evaluated by DXA at different skeletal sites in women: the OFELY cohort. J Bone Miner Res 1997;12:683-90. 8.Spector TD, Hall GM, McCloskey EV, Kanis JA. Risk of vertebral fracture in women with rheumatoid arthritis. BMJ 1993;306:558.
9.Hall GM, Daniels M, Doyle DV, Spector TD. The effect of hormone replacement therapy on bone mass in rheumatoid arthritis treated with and without steroids. Arthritis Rheum 1994; 10.Ralston SH, Hacking L, Willocks L, Bruce F, Pitkeathly DA. Clinical, biochemical and radiographic effects of aminohydroxypropylidene bisphosphonate treatment in rheumatoid arthritis. Ann Rheum Dis 1989;48:396-9. 11.Eggelmeijer F, Papapoulos SE, Van Paassen HC, et al. Increased bone mass with pamidronate treatment in rheumatoid arthritis: results of a three-year randomized, double-blind trial. Arthritis Rheum 1996;39;396-402. 12.Senior K. Osteoclast inhibitor may limit bone cancer pain. Lancet Oncology Preview 2000; Suppl: 6.
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