Juvenile systemic lupus erythematosus is a multisystem autoimmune condition characterized by chronic inflammation and by the presence of autoantibodies. Although patients with juvenile SLE comprise only 15–20% of all SLE patients, it has been suggested that they have more severe disease than adults with SLE, necessitating more frequent use of high-dose corticosteroids (1). Despite the more severe disease course of juvenile SLE, however, there has been significant improvement in long-term mortality. Therefore, more studies have focused on long-term morbidities, specifically, premature atherosclerosis and osteoporosis leading to insufficiency fractures (2–4).
Osteoporosis, an illness generally associated with postmenopausal women, is characterized by loss of both bone mass and microarchitectural integrity (5). One crucial determinate in the development of osteoporosis is the acquisition of appropriate peak mass in late adolescence and early adulthood (6). A failure to achieve adolescent peak bone mass may be associated with premature osteoporosis and increased risk of fracture. The development of peak bone mass is the result of interactions between nutritional factors including calcium intake, environmental exposures, physical activity, and medications (7, 8). Of particular concern with regard to children with chronic rheumatic diseases are the detrimental effects of chronic inflammation and corticosteroid use (9–13). These concerns are particularly important in juvenile SLE, since these patients tend to have severe chronic inflammation and frequently receive prolonged courses of high-dose corticosteroid therapy. Despite these concerns, there have been few studies examining osteoporosis and the development of fragility fractures in patients with juvenile SLE (2, 14–16). The aim of the present study was to identify risk factors associated with osteoporosis in this patient population.
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Osteoporosis is a systemic skeletal disorder characterized by low bone mass and microarchitectural deterioration of bone tissue, leading to increased bone fragility and fracture (26). Although osteoporosis is a well-known complication of adult-onset SLE, few studies have been performed in juvenile SLE (2, 14–16). In contrast to studies of juvenile dermatomyositis (11) and juvenile idiopathic arthritis (9, 12, 13, 27, 28), which have shown decreased BMD in these patients, only 2 of 4 studies of juvenile SLE demonstrated decreased BMD (14, 16). In this study, we found that osteopenia and osteoporosis at the lumbar spine and low hip BMD were common in patients with juvenile SLE, occurring in 38%, 20%, and 19% of patients, respectively. The major difference between our study and previous investigations in juvenile SLE is that the sample size of pediatric patients in our study was larger than those in the earlier studies in which lower BMD in patients with juvenile SLE was also demonstrated (14, 16). Consistent with our results were the findings of 2 studies of patients who were >19 years old at the time of study but whose SLE had begun during childhood, both of which demonstrated decreased BMD (2, 14). While the frequency of osteopenia was comparable (14), the frequency of osteoporosis was higher in our study, in which the population was exclusively pediatric.
Because the results of previous work in adults with SLE have suggested that both chronic inflammation and corticosteroid therapy are associated with decreased BMD, we examined the contributions of these factors to osteopenia and osteoporosis in order to better understand the pathogenesis of decreased BMD in patients with juvenile SLE. We did not find that the cumulative dose of corticosteroids or duration of corticosteroid use was an important predictor of lumbar spine osteoporosis or hip BMD <80%. However, cumulative corticosteroid dose was associated with lumbar spine osteopenia by multivariate analysis, although the low odds ratio suggested that the contribution was minor.
Two previous studies in juvenile SLE showed that BMD was correlated with cumulative corticosteroid dose, but the study populations included adults with childhood-onset SLE, as well as children (2, 14). Consistent with our findings are the results of studies in adult premenopausal patients with SLE, in which decreased BMD was not found to be correlated with corticosteroid use, total corticosteroid dose, or duration of corticosteroid use (29–37). Investigations of pediatric patients with nephrotic syndrome have yielded conflicting results regarding the role of corticosteroids in the development of osteoporosis (38, 39). One reason for the disparate findings regarding the role of corticosteroids in osteoporosis might relate to the fact that prolonged high-dose steroid therapy may lead to increases in weight and BMI, which may be associated with secondary improvement of spinal bone mineral content. Further studies are needed to confirm our findings of the lack of association of osteoporosis with corticosteroid use in juvenile SLE.
Studies in adults with SLE have suggested that the decreased BMD is related to disease damage and disease duration, rather than to measures of disease activity or severity (30, 32–34, 36). In the present study, univariate analysis showed multiple measures of disease activity, specific disease manifestations, and therapies to be associated with the 3 measures of abnormally low BMD. However, multivariate analysis revealed that only disease duration was associated with lumbar spine osteoporosis and decreased hip BMD. The only measure of disease activity that approached statistical significance was the association of lupus nephritis as a predictor of lumbar spine osteoporosis. The role of this variable must be analyzed carefully and may require further study. Interestingly, whether the nephritis was active or inactive at the time of BMD measurement did not affect this finding. Previous studies of patients with juvenile SLE failed to show a relationship between BMD and measures of disease activity, severity, or damage (2, 14–16).
Consistent with studies in adults with SLE (33, 34), we did not find that scores on global measures of disease activity, including the SLEDAI, ECLAM, and adjusted mean SLEDAI, were significantly associated with low BMD, despite evidence that these indices are good measures of disease activity in juvenile SLE (40–42). Although we found that many surrogate measures of disease severity, including use of immunosuppressive agents and disease damage score (as measured by SDI), were significantly associated with BMD by univariate analysis, none of these measures was significantly associated with BMD by multivariate analysis. Our finding of a lack of association with measures of disease damage in multivariate analysis contrasts with the results of studies in adult SLE (30, 32–34, 36). Our results suggest that factors other than disease damage or severity may be more important in determining BMD in juvenile SLE. However, these findings might also be explained by a lack of power in our analysis, given the sample size.
To date, there has not been a standard way of describing BMD results or defining osteopenia and osteoporosis in pediatric patients with rheumatic diseases (2, 16). Definitions of osteopenia and osteoporosis in adults (43) have been validated by epidemiologic studies correlating each standard deviation decrease in BMD with an increase of fracture risk, in postmenopausal women (44–46). The validity of using Z scores and definitions of adult osteopenia and osteoporosis in pediatric patients has been demonstrated in a study of patients with juvenile dermatomyositis (47). In the present work we report lumbar spine BMD as Z scores since these values were available for this site in our patients. Hip BMD is reported as percentages, since validated Z scores were not available. At our institution, hip BMD of 80–90% is considered a mild decrease (equivalent to a Z score of approximately −1 to −2 in adults), 70–80% a moderate decrease, and <70% a marked decrease. Therefore, we chose 80% (0.8) as a cutoff for defining abnormal hip BMD in the present study. We suggest that in general, the definitions of osteopenia and osteoporosis used in adults, i.e., scores of <−1 and <−2.5, respectively, should be used in patients with pediatric rheumatic diseases. However, a large collaborative study is needed to confirm that these cutoffs define increased risk of fracture in children, as has been done in postmenopausal women.
A limitation of our study was the use of BMD, which does not take into account structural properties of bone (5, 25). It would have been of benefit to have data regarding microarchitecture and mineralization of the bones, but we could not justify performing bone biopsy, nor did we have access to quantitative measures obtained by computed tomography or magnetic resonance imaging. However, DXA data can be readily extrapolated to clinical practice. Another limitation of our study was the lack of data on calcium and vitamin D intake, due to the retrospective design of the study. Although calcium supplementation has been shown to be of benefit in maintaining normal BMD increase in healthy prepubertal children (7), studies of children with rheumatic diseases have yielded conflicting results (14, 16, 48–50). Similarly, we did not evaluate the effect of activity on BMD, due to the retrospective study design. Although regular exercise is known to increase BMD in healthy children (51–53), studies in patients with pediatric rheumatic diseases have had conflicting results (16, 28). Prospective studies are needed to determine the effects of calcium and vitamin D intake and exercise on BMD and fracture risk in juvenile SLE.
Our study demonstrated rates of osteopenia and osteoporosis at the lumbar spine of 38% and 20%, respectively, and a 19% rate of decreased hip BMD. These findings are similar to those in previous investigations of adult SLE (29–37). We suggest that, pending future studies examining the association of fracture risk and BMD in pediatric patients, the definitions of osteopenia and osteoporosis used in adults, i.e., −1 and −2.5, respectively, should be used. Disease duration and possibly lupus nephritis (not necessarily active at the time of DXA) were identified as predictors of low BMD, suggesting that patients with juvenile SLE, and in particular those with nephritis, are at risk of osteoporosis and possibly fracture. However, since the long-term safety of antiresorptive agents has not been established in pediatric patients, we do not advocate the routine use of these agents to prevent osteoporosis in children with longstanding SLE. Long-term studies are needed to determine the morbidity associated with osteoporosis in juvenile SLE and the role of prophylactic therapy to prevent this complication.
- Top of page
- PATIENTS AND METHODS
- AUTHOR CONTRIBUTIONS
Dr. Silverman had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study design. Compeyrot-Lacassagne, Gilday, Silverman.
Acquisition of data. Compeyrot-Lacassagne, Tyrrell, Gilday, Silverman.
Analysis and interpretation of data. Compeyrot-Lacassagne, Tyrrell, Atenafu, Doria, Stephens, Silverman.
Manuscript preparation. Compeyrot-Lacassagne, Tyrrell, Atenafu, Stephens, Silverman.
Statistical analysis. Atenafu, Stephens.