Bone loss in ankylosing spondylitis: can we put the puzzle together?

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-α (TNF-α), 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.