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Editorial
Bone Loss in Ankylosing Spondylitis: Can We Put the Puzzle Together?
DANIEL WENDLING, MD, PhD,
Ankylosing spondylitis (AS) raises the paradox of a disease characterized by new bone formation at sites of chronic inflammation and the association of reduced bone mass and increased fracture risk. For several years it has been established that bone mineral density (BMD) loss occurs early in the AS disease course and is associated with inflammation correlated with increased bone resorption1,2. Recent reports confirm reduction of BMD at the hip and femoral neck3, and a vertebral fracture rate of 0.4% at a mean age of 50 ± 9 years, occurring after 2 decades of disease, with possible neurological complications4. In this issue of The Journal, Karberg and colleagues5 report that bone loss is more frequently detected in AS patients with syndesmophytes. Their study confirms reduction of BMD in a cohort of AS patients. Bone loss was apparent using different devices and techniques and at different sites of evaluation [dual energy x-ray absorptiometry (DEXA) at the lumbar spine and femur, dual energy quantitative computerized tomography (CT) at the lumbar spine, and peripheral quantitative CT at the forearm]. The results with different techniques were not correlated. Their findings concur with our ultrasound measurements at the calcaneus1, whereas Jansen, et al6 using quantitative ultrasound of the heel were able to identify AS patients with osteoporosis associated fracture. Karberg, et al found that DEXA at the femoral neck was the most sensitive method for evaluating osteopenia and osteoporosis in AS, even in patients without syndesmophytes. This method and site were also felt to be the most accurate in AS for British rheumatologists7. Measurement at the femur avoids bias represented by enthesis ossification (namely syndesmophytes) in posteroanterior lumbar spine assessment. Syndesmophytes have no distorting effect on BMD measured by lateral DEXA8. Reduction of BMD was greater in AS patients with syndesmophytes; and although, as expected, these patients exhibited a longer duration of disease, there was no correlation between BMD and disease duration; moreover, in the presence of syndesmophytes more patients were seen to have decreased BMD, even those with short disease duration. Recently, Lange9 confirmed decreased bone density even at the initial stage of AS and continuing into the advanced stages; this was observed not only in the spine but also at the femoral neck. It would be interesting to add to the results of Karberg by quantifying syndesmophytes (using the modified Stoke AS Spine Score, for instance) to look for a correlation between BMD reduction and syndesmophyte score. A correlation would underline the responsibility of an (un)coupling process between bone decrease (resorption) and syndesmophyte formation. This would allow a new interpretation of these observations, which is still under debate. In AS, the pathological process begins at the enthesis: local inflammation is followed by ligament ossification involving potentially proinflammatory cytokines [interleukin 6 (IL-6), tumor necrosis factor-a (TNF-a), IL-1] and growth factors [transforming growth factor-ß (TGF-ß), insulin-like growth factor (IGF)]. These local phenomena are difficult to investigate due to the poor accessibility of the enthesis. Bone loss is evident adjacent to areas of enthesis inflammation, but, as a systemic disease, there is also evidence of bone loss at clinically uninvolved sites like femoral neck in the study of Karberg. WHAT UNDERLYING PHYSIOPATHOLOGICAL MECHANISMS LEAD TO BONE LOSS IN AS? The available puzzling data originate from studies evaluating systemic modifications of factors involved at different stages of bone loss. Bone histomorphometric studies are scant. Szejnfeld, et al studied 16 patients with AS: osteopenia was found in 14 patients, mineralization defect in 10, and osteomalacia in 3 patients10. Moreover, there was a positive correlation between measures of osteomalacia (osteoid volume, mineralization lag time) and disease duration, and a negative correlation between disease duration and resorption (eroded surface, bone osteoclast interface), suggesting a biphasic mechanism. Low BMD in AS is associated with increased biochemical markers of bone turnover, especially resorption, such as deoxypyridinoline (DPD); in fact DPD levels have been found to be correlated in AS with inflammation assessed by erythrocyte sedimentation rate or C-reactive protein (CRP)1,3. The latter may reflect severity and evolution of disease and therefore be compatible with accelerated syndesmophyte formation, irrespective of disease duration, as in the study reported by Karberg. However, the authors did not find a correlation between DPD and clinical or biological activity of the disease, as assessed by Bath AS Disease Activity Index and CRP. This apparent discrepancy can be explained: serum levels of biological markers reflect the situation at a given timepoint, whereas radiological features such as syndesmophytes or BMD values reflect the cumulative influence of the disease over time. Other factors may be involved. Genetic factors have been suspected, and there is evidence that vitamin D receptor gene may contribute to BMD differences, bone metabolism, and inflammation processes in AS11. The role of reduced physical activity in AS patients with syndesmophytes is discussed in the article by Karberg, and is probably not predominant. Hormones may also play a part. Franck, et al3 demonstrated a positive correlation between BMD at the femoral neck and free testosterone serum levels in AS men and free estradiol serum levels in AS women. Cytokines represent a link between local and systemic inflammation on the one hand, and bone resorption and BMD reduction on the other. Il-6 and TNF-a, which are involved in AS inflammation, are osteoclast activators12, whereas consistent modification of growth factor (TGF-ß, IGF) serum levels have not been demonstrated1,13. Finally, the RANK-RANK ligand system and its natural inhibitor osteoprotegerin (OPG) may represent the key point in bone-cytokine interrelation. Franck3, et al found significantly lower serum OPG levels in AS patients compared to controls; this finding was unrelated to age, suggesting a lack of this resorption antagonist in AS. Further investigation in this area might include soluble RANK ligand levels and correlation with biological inflammation. IL-17 (and its receptor) is a good candidate for the missing piece of the puzzle14. IL-17 is a T cell cytokine exhibiting proinflammatory properties by triggering expression of inflammatory effectors that promote osteoclastogenesis and bone destruction. IL-17 may enhance chemotactic factors (granulocyte macrophage-colony stimulating factor, monocyte chemotactic protein, IL-8) that promote neutrophil recruitment and activation, which can exert both bone protective and destructive effects. In vivo bone erosion mediated by overexpression of IL-17 has been shown to occur through alterations in the RANKL/OPG ratio15. Bone loss in AS appears to be multifactorial and perhaps involves different mechanisms at different stages of disease. Nevertheless, and beyond hypotheses, BMD reduction in AS is a reality that should be taken into account in the management of these patients, particularly since the advent of new therapeutic opportunities (anti-TNF agents) able to improve both disease activity and BMD16. 2. El Maghraoui A. Osteoporosis and ankylosing spondylitis. Joint Bone Spine 2004;71:291-5. [MEDLINE] 3. Franck H, Meurer T, Hofbauer LC. Evaluation of bone mineral density, hormones, biochemical markers of bone metabolism, and osteoprotegerin serum levels in patients with ankylosing spondylitis. J Rheumatol 2004;31:2236-41. [MEDLINE] 4. Vosse D, Feldtkeller E, Erlendsson J, Geusens P, Van Der Linden S. Clinical vertebral fractures in patients with ankylosing spondylitis. J Rheumatol 2004;31:1981-5. [MEDLINE] 5. Karberg K, Zochling J, Sieper J, Felsenberg D, Braun J. Bone loss is detected more frequently in ankylosing spondylitis patients with syndesmophytes. J Rheumatol 2005;32:1290-8. 6. Jansen TLT, Aarts MHM, Zanen S, Bruyn GAW. Risk assessment for osteoporosis by quantitative ultrasound of the heel in ankylosing spondylitis. Clin Exp Rheumatol 2003;21:599-604. [MEDLINE] 7. Bessant R, Harris C, Keat A. Audit of the diagnosis, assessment, and treatment of osteoporosis in patients with ankylosing spondylitis. J Rheumatol 2003;30:779-82. [MEDLINE] 8. Gilgil E, Kaçar C, Tuncer T, Bütün B. The association of syndesmophytes with vertebral bone mineral density in patients with ankylosing spondylitis. J Rheumatol 2005;32:292-4. [MEDLINE] 9. Lange U, Kluge A, Strunk J, Teichmann J, Bachmann G. Ankylosing spondylitis and bone mineral density — what is the ideal tool for measurement? Rheumatology Int 2005; published online: 5 Nov 2004. [MEDLINE] 10. Szejnfeld VL, Monier-Faugere MC, Bognar BJ, Ferraz MB, Malluche HH. Systemic osteopenia and mineralization defect in patients with ankylosing spondylitis. J Rheumatol 1997;24:683-8. [MEDLINE] 11. Obermayer-Pietsch BM, Lange U, Tauber G, et al. Vitamin D receptor initiation codon polymorphism, bone density and inflammatory activity of patients with ankylosing spondylitis. Osteoporosis Int 2003;14:995-1000. [MEDLINE] 12. Walsh NC, Gravallese M. Bone loss in inflammatory arthritis: mechanisms and treatment strategies. Curr Opin Rheumatol 2004;16:419-27. [MEDLINE] 13. Lange U, Teichmann J, Stracke H. Correlation between plasma TNF-alpha, IGF-1, biochemical markers of bone metabolism, markers of inflammation/disease activity, and clinical manifestations in ankylosing spondylitis. Eur J Med Res 2000;5:507-11. [MEDLINE] 14. Graffen SL. Biology of recently discovered cytokines: interleukin-17 — a unique inflammatory cytokine with roles in bone biology and arthritis. Arthritis Res Ther 2004;6:240-7. [MEDLINE] 15. Lubberts E, Van Der Bersselaar L, Oppers-Walgreen B, et al. IL-17 promotes bone erosion in murine collagen-induced arthritis through loss of the receptor activator of NF-kappa B ligand/osteoprotegerin balance. J Immunol 2003;170:2655-62. [MEDLINE] 16. Briot K, Garnero P, Le Henaff A, Dougados M, Roux C. Body weight, body composition and bone turnover changes in patients with spondyloarthropathy receiving anti-tumour necrosis factor-a therapy. Ann Rheum Dis 2005; published online January 7, 2005: doi:10.1136/ard.2004.028670 [MEDLINE] |
