Risk factors for diffuse idiopathic skeletal hyperostosis: a casecontrol study
C. Kiss,
M. Szilágyi,
A. Paksy1 and
G. Poór
National Institute of Rheumatology and Physiotherapy, Budapest and
1 Semmelweis University, Budapest, Hungary
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Abstract
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Objective. Diffuse idiopathic skeletal hyperostosis (DISH) is a skeletal disease characterized by ligamentous ossification of the anterolateral side of the spine. The aim of this study was to characterize risk factors associated with DISH.
Methods. Subjects were recruited for participation in a screening survey of vertebral osteoporosis. The cases were 69 men and 62 women with DISH and the controls were 69 men and 62 women with spondylosis over the age of 50 yr. Cases and controls were matched for age and sex. Radiographs were taken according to a standardized protocol and DISH was classified using the Resnick criteria. Laboratory parameters and an interviewer-administered questionnaire were used to obtain data about exposure.
Results. The mean ages of the populations with DISH and spondylosis were 65.2±8.8 and 65.0±9.1 yr respectively. Compared with controls, patients with DISH had a greater body mass index (27.8 vs 26.0 kg/m2, P<0.05) and a higher serum level of uric acid (308 vs 288 µmol/l, P<0.05) and were more likely to have had diabetes mellitus (19.8 vs 9.1%, P<0.05).
Conclusion. DISH is clearly a distinct disorder with risk factors that distinguish it from other spinal degenerative diseases.
KEY WORDS: Casecontrol study, Diffuse idiopathic skeletal hyperostosis, Spondylosis.
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Introduction
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Diffuse idiopathic skeletal hyperostosis (DISH, ankylosing hyperostosis) is a common skeletal disease of unknown aetiology seen in middle-aged and elderly patients. The principal manifestation of DISH is ligamentous ossification of the anterolateral aspect of the spinal column, sometimes leading to bony ankylosis. DISH frequently involves the spine in other anatomical sites, and peripheral entheseal ossification and bony spurs have also been reported. Pain, stiffness, dysphagia and neurological abnormalities are the main clinical features of DISH [1, 2]. DISH is more frequent in males and the prevalence increases with age, affecting mainly subjects over the age of 40 yr [3]. The aetiology of the disease is unknown. There are few controlled clinical studies of DISH [4, 5]. Metabolic, endocrine, genetic and environmental factors have been proposed as being important in pathogenesis. Several authors have reported an association with metabolic disorders [6, 7]. Some, though not all, have found associations with gout, rheumatoid arthritis and diabetes mellitus [3, 8, 9].
The aim of the study was to determine risk factors associated with DISH in a population sample of men and women. We used a matched casecontrol design in which individuals with lumbar spondylosis were used as the controls.
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Materials and methods
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Patients with DISH and patients with spondylosis were selected from participants in a screening survey of vertebral osteoporosis, the European Vertebral Osteoporosis Study (EVOS), which is a multinational, cross-sectional study in 19 European countries of men and women aged over 50 yr. In Budapest, subjects were recruited from a health register from district III of Budapest. For all subjects, an interviewer administered a questionnaire and a lateral spinal radiograph was made. All radiographs were reviewed and individuals with DISH were identified using the criteria of Resnick et al. [10] (Table 1
). Controls were subjects with moderate to severe spondylosis and were matched for age and sex with the DISH cases. A modified Kellgren and Lawrence [11] grading system was used to assess radiographic changes in spondylosis. All subjects had blood taken and the following measurements were made: serum uric acid, cholesterol, triglyceride and glucose. Measurement of serum uric acid was detected by an enzyme method (Trinder reaction) with the Fabio 80001 kit (Fabio, Budapest, Hungary). Serum cholesterol, triglyceride and glucose were measured colorimetrically, using the cholesterol oxidase-para amino phenazone, glycerol phosphate-para amino phenazone and glucose oxidase-para amino phenazone reactions respectively. The upper normal levels of these serum variables were as follows: glucose 5.5 mmol/l, triglyceride 2.2 mmol/l, cholesterol 5.6 mmol/l, and uric acid 420 µmol/l for males and 360 µmol/l for females.
The EVOS questionnaire included questions about weight and height at the age of 25 yr, accompanying illnesses, alcohol, calcium intake and smoking habits. For alcohol consumption, the participants were asked Which of the statements comes closest to describing how often you drank any alcoholic beverages in the past year?, and the possible responses were: every day; 56 days per week; 34 days per week; 12 days per week; less than once a week; and not at all. For smoking, participants were asked Do you smoke cigarettes or another form of tobacco?, and the possible responses were: yes, now; not now but in the past; and never. For calcium intake, participants were asked How often in the past week did you eat hard cheese, soft cheese, yogurt, milk, ice cream and how often did you drink milk up to 25 yr, aged 2550 yr, from age 50 onwards?, and the possible responses were: at every meal; every day; every week; less than once a week. Current height and weight were measured using standard methods. The body mass index (BMI) was calculated as kg/m2. Student's paired t-test was used for continuous and the McNemar test for categorical variables. We calculated the correlation coefficient between BMI and serum level of uric acid in the cases and controls. Multivariate analysis was carried out, including BMI, serum uric acid level and diabetes mellitus in the medical history.
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Results
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A total of 635 subjects were recruited in the EVOS and the radiographs of 131 patients (69 males and 62 females) affected by DISH were identified according to the Resnick criteria. The mean ages of the populations with DISH and spondylosis were 65.3 (S.D. 8.8) yr (range 5287) and 65.0 (9.1) yr (range 5088) respectively. The anthropometric factors are detailed in Table 2
. The patients with DISH were significantly heavier at the age of 25 yr and currently than the spondylosis patients (
Fig. 1). Weight gain from age 25 yr to the present was somewhat greater in the DISH group.
Data on lifestyle factors are reported in Table 2
. There were no significant differences in the intake of the main calcium-containing food items (hard cheese, soft cheese, yogurt, other milk products, milk). Alcohol intake and the frequency of smoking were similar in the two groups. Data on associated diseases are reported in Table 3
. The frequencies of hypertension and cardiovascular disease were similar in the two patient groups. Non-insulin-dependent diabetes mellitus (NIDDM) was more frequent in the DISH patients (19.8 vs 9.1%, P<0.05). The laboratory data are presented in Table 3
. Those with DISH had higher levels of serum uric acid than the spondylosis group (308±85 vs 288±102 µmol/l, P=0.048), but we did not find a significant difference between the groups in the frequency of hyperuricaemia. There was no correlation between BMI and serum level of uric acid in the DISH group (correlation coefficient 0.129, P=0.15), but these two variables were correlated in the spondylosis group (correlation coefficient 0.203, P=0.02). In the multivariate analysis DISH was significantly associated with BMI (P=0.03) but not with serum uric acid level or diabetes mellitus in the medical history. There was no significant difference in serum total cholesterol, triglyceride, and glucose levels between the cases and controls.
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Discussion
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DISH is a chronic degenerative skeletal disease but only in the last few years has it been the object of detailed studies [3, 9]. The diagnosis of DISH is usually based on radiographic assessment. Most, but not all, of the published studies have been performed on clinic-based subjects and may not therefore be extrapolated to the community [12]. Our patients were recruited with a population-based sampling frame. It has been suggested that DISH is a state or radiographic finding rather than a disease [13]. The present study was designed to assess whether there are anthropometric or metabolic correlations unique to DISH. Our study provides strong support for the hypothesis that DISH is a distinct disorder. We have found differences in BMI, the occurrence of diabetes mellitus in the medical history, and the serum level of uric acid in DISH patients compared with a group of spondylotic controls. We studied a spondylotic control group rather than a normal population group because there are authors who consider DISH to be a form of spondylosis [5]. It is possible that the diabetics in the population were treated properly and this is why the frequency of hyperglycaemia did not differ significantly between the cases and the controls. We found that there was a significantly higher level of serum uric acid in the DISH group. Interestingly, this higher concentration was not associated with BMI in the DISH group. This suggests that obesity is not the reason for the elevated serum uric acid level in DISH. Others, however, have shown no differences in several metabolic parameters, including the concentrations of glucose, uric acid and cholesterol, between patients with DISH and controls matched for age, sex and BMI [4]. Thus, the association of DISH with insulin remains uncertain. We and others have found that subjects with DISH were more obese than spondylosis control patients at the age of 25 yr as well as currently [5]. DISH patients weigh more today because they weighed more when they were young and weighed more thereafter. This suggests that obesity at an early age and later in life is a strong risk factor for DISH.
The aetiology of vertebral hyperostosis is unclear. It is not related primarily to degenerative disease of the spine [14]. Marked hyperinsulinaemia has been demonstrated in patients with DISH [15]. This seems to reflect the increased prevalence of obesity and diabetes in patients with DISH. Hyperinsulinaemia is also common in gouty, hyperuricaemic patients [7]. Thus hyperinsulinaemia, possibly related to obesity, may be the factor linking metabolic parameters with the development of vertebral hyperostosis.
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Conclusion
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This is the first matched pair casecontrol study of DISH to be published. DISH patients were more likely to report a history of diabetes mellitus, weighed more at a young age, put on more weight, and their BMI was greater at the time of clinical evaluation than that of spondylosis patients. Differences were found among the groups of patients for the laboratory variables evaluated. DISH is clearly a distinct disorder with factors that distinguish it from other causes of spinal degenerative diseases. Further investigation is needed to elucidate its aetiology.
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Acknowledgments
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As members of EVOS, we would like to thank the project leader, Alan Silman, for valuable help in planning the EVOS Budapest population study and for the EVOS questionnaire used in this study. Correction of the manuscript by Terence O'Neill is highly appreciated.
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Notes
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Correspondence to: C. Kiss, National Institute of Rheumatology and Physiotherapy, Frankel Leó str. 3840, Budapest, Hungary. 
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Submitted 5 December 2000;
Accepted 26 June 2001