Ankylosing spondylitis (AS) is characterized by inflammation

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1 ORIGINAL ARTICLE Is Osteoporosis Generalized or Localized to Central Skeleton in Ankylosing Spondylitis? Selda Sarikaya, MD, Aynur Basaran, MD, Yasin Tekin, MD, Senay Ozdolap, MD, and Ozgur Ortancil, MD Background: Osteoporosis at the lumbar spine and at the femur is a well-established complication in ankylosing spondylitis (AS), but the exact mechanism and the distribution of osteoporosis are not known absolutely. Objective: To determine whether the osteoporosis is generalized or localized to central skeleton and to examine the relation between bone mineral density (BMD) and disease activity and radiologic progression in patients with AS. Methods: In this study, 26 patients with AS and 33 healthy controls matched for age and sex were recruited to the study. Hip and forearm BMD were measured by dual energy X-ray absorptiometry (DEXA). Laboratory and clinical disease activity parameters were documented, and anteroposterior sacroiliac radiographs were taken to determine the radiologic progression. Results: The urine deoxypyridinoline levels of the patients with AS were statistically significantly higher (P 0.02) and the serum osteocalcin levels were significantly lower with respect to controls (P 0.03). The femoral neck and femur BMD values and T scores were significantly lower in patients with AS compared with the controls (P 0.019, 0.003, 0.01, and 0.01, respectively). The differences in BMD values and T scores of the distal 1/3 radius between 2 groups were not statistically significant. The relation between BMD and disease activity, and radiologic progression in patients with AS could not detected. Conclusion: Sparing of distal regions such as the as radius suggests that osteoporosis might be due to localized effects of inflammatory activity or immobility rather than a systemic effect. Both increased resorption and decreased formation might be involved in the pathogenesis of osteoporosis. Radius BMD may not be appropriate to evaluate bone loss in patients with AS. Key Words: ankylosing spondylitis, osteoporosis, central skeleton (J Clin Rheumatol 2007;13: 20 24) From the Department of Physical Medicine and Rehabilitation, Zonguldak Karaelmas University Faculty of Medicine, Zonguldak, Turkey. Reprints: Dr. Aynur Basaran, Zonguldak Karaelmas Üniversitesi Tıp Fakültesi, Fiziksel Tıp ve Rehabilitasyon Anabilim Dalý, Zonguldak 67600, Turkey. abasaran@med.karaelmas.edu.tr or aynurbasaran@ hotmail.com. Copyright 2007 by Lippincott Williams & Wilkins ISSN: /07/ DOI: /01.rhu Ankylosing spondylitis (AS) is characterized by inflammation of entheses and paravertebral structures leading to bone formation at those sites. 1 Early vertebral bone loss is also a recognized feature of AS, 2 and seems to be associated with severe complications such as vertebral fractures and increased spinal deformity. 3,4 Syndesmophytes and spinal ossifications may result in false increase in bone mineral density (BMD) assessed by conventional posteroanterior dual energy X-ray absorptiometry (DEXA) 5 and may be insufficient to show osteoporosis. Currently, femoral DEXA is thought to be the most accurate method for diagnosis of osteoporosis in AS. 5 8 Similar to other inflammatory arthritides, the role of different factors in the pathogenesis of osteoporosis such as treatment, mobility or physical activity, hormone status, or even the inflammatory process, is not defined completely in AS. 7,9 13 Factors involving local and/or systemic inflammation might result in osteoporosis. Exact mechanism leading to bone loss in vertebrae and new bone formation in syndesmophytes concomitantly is not known. Therefore, it has been suggested the pathologic processes of resorption and bone formation may well occur in close proximity. 8,14 In this study, we aimed to measure hip and forearm BMD with DEXA, to determine whether the osteoporosis is generalized or localized to the central skeleton, to examine bone metabolism and disease activity in AS patients. Also the relation between bone metabolism, BMD, disease activity, and radiologic progression was investigated. MATERIALS AND METHODS During the study period of , 26 patients (5 women, 21 men) diagnosed as AS according to the Modified New York criteria 15 and age- and sex-matched 33 healthy controls (13 women, 20 men) were recruited to the study. Patients with metabolic bone disease (such as Paget disease, osteomalacia, hyperparathyroidism), chronic renal, hepatic and thyroid disease, hormone disorders, medication affecting bone metabolism (such as corticosteroids, bisphosphonates), and postmenopausal women were excluded. In this study, AS patients with peripheral arthritis were excluded. All patients and the control group had sedentary lifestyles with low physical activity (e.g., office workers, housewives). BMD was measured from hip and forearm on the nondominant side by DEXA (Hologic QDR 4500W, Hologic, Bedford, MA), which has a mean precision error of 1% for 20 JCR: Journal of Clinical Rheumatology Volume 13, Number 1, February 2007

2 JCR: Journal of Clinical Rheumatology Volume 13, Number 1, February 2007 Osteoporosis in Ankylosing Spondylitis the forearm and hip. The reference values of BMD for women and men were provided by the manufacturer. The results were recorded as g/cm 2 and T score. T scores 1 were classified as normal, 1 and 2.5 were classified as osteopenia, and 2.5 were classified as osteoporosis according to World Health Organization (WHO) osteoporosis classification. 16 The femur T score accepted was the lowest value measured anywhere except the Ward triangle. The laboratory activity was assessed by erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), the clinical disease activity was evaluated by Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), 17 and the functional status measurement was made by Bath Ankylosing Spondylitis Functional Index (BASFI). 18 An anteroposterior radiograph of the pelvis was taken in all patients with AS. Radiologic progression was evaluated by Bath Ankylosing Spondylitis Radiology Index (BASRI). 19 A single investigator assessed all radiographs. Serum concentrations of osteocalcin (OC), parathyroid hormone (PTH), calcium and phosphate and urinary deoxypyridinoline (DPD) and daily urinary calcium excretion levels were measured to evaluate the bone metabolism. Samples for serum and second voided urine were collected at 8:00 to 10:00 a.m. after overnight fasting. Urine is collected for the measurement of urine calcium excretion. Serum samples were stored at 40 C until assayed. Serum calcium and phosphate were measured using spectrophotometry (Cobas Integra 800, Roche, Indianapolis, IN). The OC and PTH levels were determined using a chemiluminescent immunoassay (Elecsys 2010, Roche). Urine DPD was measured with a solid phase chemiluminescent enzyme labeled immunoassay (Immulite One, BioDPC). ESR was determined by the Westergreen method. CRP was determined by latex agglutination method (Plasmatec, UK). Sample size calculation was performed according to T scores between 2 groups. To detect a difference of 0.2, 34 patients (17 patients in each group) were required (P 0.05, power 0.80). Parametric and nonparametric variables between patients were compared using Student t test for independent samples and Mann Whitney U test, respectively. 2 test was used for frequencies in cross-tables. Pearson r and Spearman correlation coefficients were used to assess correlations among laboratory and clinical disease activity parameters, functional status, bone turnover markers, BMD of hip, and T scores, as appropriate. Statistical calculations were performed using SPSS for Windows 11.5 (SPSS Inc.). Statistical significance level was set to TABLE 1. Clinical and Laboratory Characteristics of AS Patients and Controls AS (n 26) Controls (n 33) P Age (y) BMI (kg/m 2 ) DPD (nm/mm 6.10 ( ) 5.0 ( ) 0.02 creatinine)* OC (ng/ml) Calcium (mg/dl) Phosphorus (mg/dl) Urine calcium/d (mg/24 h) PTH (pg/ml) CRP (mg/l)* 0 (0 4) 0 (0 1) ESR (mm/h) AS: ankylosing spondylitis; BMI: body mass index; DPD: deoxypyridinoline; OC: osteocalcin; PTH: parathyroid hormone; CRP: C-reactive protein; ESR: erythrocyte sedimentation rate. *Median (min max). All other values were expressed as mean SD. Statistically significant. RESULTS Clinical and laboratory characteristics of patients and controls are summarized in Table 1. The urine DPD levels of the patients with AS were statistically significantly higher than those in the control subjects (P 0.02). The serum OC levels were significantly lower with respect to controls (P 0.03). The differences between the serum PTH, calcium, phosphorus and urine daily calcium excretion levels were not statistically significant. The biologic markers of disease activity (CRP and ESR) were significantly higher in AS group (P and 0.002, respectively). BASDAI, BASFI, BASRI scores of AS patients were summarized in Table 2. Mean BMD values and T scores in patients with AS and control subjects are given in Table 3. The femoral neck and femur BMD values were significantly lower in patients with AS compared with the controls (P and 0.003, respectively). The difference between the femoral neck and femur T scores of 2 groups were also statistically significant (P 0.01 and 0.01, respectively) with lower levels in the AS group. The differences in BMD and T scores of distal 1/3 radius between the 2 groups were not significant. Osteoporosis classifications according to femur and radius measurements are shown in Table 4. The ratio of patients with low bone density (osteopenia and osteoporosis) at femur in AS patients (76.9%) was significantly higher than that in controls (33.3%, P 0.001). However, the difference in the ratio of low bone density at the distal 1/3 radius between the 2 groups was not significant. Correlation coefficients between bone turnover markers, biologic and clinical parameters of disease activity, functional status, hip BMD values, and T scores were analyzed. There was no correlation between biologic parameters of inflammation (CRP, ESR) and bone turnover markers (OC TABLE 2. BASDAI, BASFI, and BASRI Scores of AS Patients AS (n 26) BASDAI BASFI BASRI sacroiliac* 3.5 (2 4) BASRI lomber* 2 (1 4) AS: ankylosing spondylitis; BASDAI: bath ankylosing spondylitis disease activity index; BASFI: bath ankylosing spondylitis functional index; BASRI: bath ankylosing spondylitis radiology index. *Median (min max). All other values were expressed as mean SD Lippincott Williams & Wilkins 21

3 Sarikaya et al JCR: Journal of Clinical Rheumatology Volume 13, Number 1, February 2007 TABLE 3. Mean BMD Values and T Scores in Patients With AS and Control Subjects AS (n 26) Controls (n 33) P Total femur BMD (g/cm 2 ) * Femoral neck BMD (g/cm 2 ) * 1/3 distal radius BMD (g/cm 2 ) Femur T score * Femoral neck T score * 1/3 distal radius T score 1.50 ( 3.70 to 1.30) 1.30 ( 2.40 to 0.50) AS: ankylosing spondylitis; BMD: bone mineral density. *Statistically significant. Median (min max). All other values were expressed as mean SD. TABLE 4. Osteoporosis Classification of the Patients and Control Subjects AS (n 26) Controls (n 33) P Femur Normal (%) 6 (23.1) 22 (66.7) 0.001* Osteopenia osteoporosis (%) 20 (76.9) 11 (33.3) Radius Normal (%) 8 (30.8) 11 (33.3) 0.83 Osteopenia osteoporosis (%) 18 (69.2) 22 (66.7) AS: ankylosing spondylitis; OP: osteoporosis. *Statistically significant. and DPD). Correlation between bone turnover markers and either BASDAI or BASFI scores was not detected (all P 0.05). Additionally, there was no correlation between bone turnover markers and either femur/femoral neck BMD values or T scores (all P 0.05). There were no correlations between sacroiliac BASRI score and either femur/femoral neck BMD values or T scores (all P 0.05). DISCUSSION In inflammatory arthropathies, the mechanism of bone loss is complex and seems to be multifactorial. The factors responsible from bone loss include medication (especially corticosteroids), hormone disorders, genetics, inflammation, and decreased mobility or physical activity. 2,12,20,21 Low bone density has been well documented in patients with AS. 8,9,22,23 Clinically osteopenia or osteoporosis has been recognized in 20% 60% of patients. 8 Also it has been shown that patients with active disease without hip involvement as well as patients with hip arthritis had low BMD at the femoral neck. 2,12,24 Therefore it was hypothesized that the inflammatory process could be responsible for generalized osteoporosis. 9,25,26 In accordance with previous studies, 8,27 29 however, we did not observe low BMD at the radius. OP at the femur, while the radius is spared, might be explained by a close relationship of femur to sacroiliac joints rather than systemic inflammatory involvement, in the patients without hip arthritis. In our study, sparing of the distal radius BMD showed that osteoporosis in AS is not generalized. Local factors might also be responsible. According to these results, 22 distal radius BMD should not be used to evaluate the cortical bone loss, instead of femur BMD in AS patients for whom femur BMD was not available (difficulty in positioning, femoral arthroplasty, etc.). In our study, we have observed the incidence of osteoporosis/osteopenia ratio higher than expected values in the control group, as well as the patients. There is no study demonstrating normal values in our population. However, BMD values (g/cm 2 ) are statistically significantly lower in AS patients suggesting that there is additional bone loss in femur BMD, while the radius is spared. Although osteoporosis at the lumbar spine and femur is well established, the mechanism and factors are not known absolutely in AS. It is thought that osteoporosis in AS is related with increased bone resorption associated with inflammation The role of osteoblasts in new bone formation in AS is not defined completely. The results of crosssectional studies are contradictory. Some of the studies have documented low levels of OC, 10,34,35 while some documented normal levels, 12,36,37 and some of them documented high levels 8,38 in patients with AS. In addition to this the relationship between OC and inflammation has not been documented. 8 Recently, in a case control study of 29 patients with AS, El Maghraoui et al 39 showed that serum OC levels were significantly lower in AS patients than those in healthy controls. They hypothesized that decreased formation may play a role in the pathogenesis of osteoporosis. In our study serum OC levels were significantly lower in AS patients (P 0.03). Additionally urine DPD levels were significantly higher in AS patients than those in controls (P 0.02) consistent with previous reports. 36,37 These results suggest that decreased bone formation and increased resorption might be involved in the pathogenesis of osteoporosis in patients with AS. Studies of bone resorption markers and disease activity have shown that the excretion of pyridinoline crosslinks is correlated with ESR 36,37 and CRP 23,33 indicating that patients with active disease could have a higher risk of bone loss. These results together support that increased inflammatory activity in AS leads to increased bone resorption and thus decreased bone density. 8 Nevertheless, studies investigating for a relationship between BMD and inflammatory activity in AS patients have reported negative results. 29,36 Karberg et al 8 reported that BMD was not correlated with disease activity (assessed by BASDAI) and inflammation (measured by CRP) in 2007 Lippincott Williams & Wilkins

4 JCR: Journal of Clinical Rheumatology Volume 13, Number 1, February 2007 Osteoporosis in Ankylosing Spondylitis patients with AS. Similarly there was no statistically significant relationship between urinary DPD and the BASDAI score or CRP levels. In our study, there was no correlation between disease activity (assessed by CRP, ESR, and BASDAI score) and bone turnover (assessed by OC and DPD levels). In addition to this, there was no correlation between bone turnover markers (OC and DPD levels) and BMD (total and femoral, neck BMD values and T scores), consistent with Karberg s study. In a prospective study of Gratacos et al, with a mean follow-up of 19 months, a significant reduction in bone mass in the lumbar spine and femoral neck in patients with active AS has been documented. 9 In our study, lack of correlation between BMD and clinical or biologic activity of the disease, as assessed by BASDAI and CRP, might be explained as that serum levels of biologic markers reflect the situation at a given time point, whereas BMD values reflect the cumulative influence of the disease over time. 6 In addition to this, relatively low levels of disease activity in our patients might be responsible for these results also. El Maghraoui et al 39 showed a negative significant statistical correlation with BMD and BASMI and BASRI, which show long-term effects and severity of disease activity. However we could not demonstrate a correlation between sacroiliac BASRI score and BMD. In conclusion, osteoporosis is the result of complex pathophysiologic mechanisms involving disease activity and inflammatory process in AS. Sparing of distal regions as radius might be due to localized effects of inflammatory activity rather than systemic effect. Therefore, radius BMD measurement might not be appropriate to evaluate bone loss in patients with AS. REFERENCES 1. Gilgil E, Kacar C, Tuncer T, et al. The association of syndesmophytes with vertebral bone mineral density in patients with ankylosing spondylitis. J Rheumatol. 2005;32: Will R, Palmer R, Bhalla AK, et al. Osteoporosis in early ankylosing spondylitis: a primary pathological event? Lancet. 1989;2: Ralston SH, Urquhart GD, Brzeski M, et al. Prevalence of vertebral compression fractures due to osteoporosis in ankylosing spondylitis. BMJ. 1990;300: Cooper C, Carbone L, Michet CJ, et al. Fracture risk in patients with ankylosing spondylitis: a population based study. J Rheumatol. 1994; 21: Bessant R, Harris C, Keat A. 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