Systemic lupus erythematosus (SLE) is a chronic, inflammatory, multisystem disease for which long-term corticosteroid therapy often is required. Use of corticosteroids was a breakthrough in the treatment of SLE and has led to increased survival; however, the longer survival time has meant that these patients now experience a range of complications, some of which are attributable to the disease itself and some of which are medication side effects (1). These complications include reduced bone mass and osteoporosis, which are recognized as major health problems in patients with SLE (2).
Several studies of osteoporosis have involved adult patients with SLE (3–11), but only a few such studies have addressed childhood-onset SLE (12, 13). Bone mass increases throughout childhood and adolescence, reaching a peak in the late teens or early adulthood (14). Peak bone mass is partly genetically determined but is also influenced by hormonal factors, physical activity, and nutritional factors (15, 16). The presence of lower-than-expected peak bone mass during the period of skeletal growth increases the risk of osteoporosis and fractures later in life (17, 18).
Several other factors are associated with the risk of osteopenia in patients with SLE, including inflammation, renal failure, ovarian dysfunction, lack of sun exposure (due to conscious avoidance), and intake of corticosteroids (19, 20). Endocrinologically, cortico-steroids are known to adversely affect bone mass through decreased formation and increased resorption of bone (21, 22), but the impact of corticosteroids on bone loss in the setting of SLE is unclear (6, 9, 10, 19).
We evaluated the frequency of osteopenia in a cohort of Norwegian patients with childhood-onset SLE and compared it with that in healthy age- and sex-matched controls. We also investigated the relationship between disease-related variables and bone mass in the lumbar spine, femoral neck, total body, and forearm.
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- PATIENTS AND METHODS
In the present cohort of 70 patients with childhood-onset SLE with a mean disease duration of 10.8 ± 8.3 years, BMD in the lumbar spine and femoral neck was significantly lower than that in matched healthy controls. We also found that in our patients with childhood-onset SLE, a higher cumulative corticosteroid dose was significantly associated with a lower bone mass in the lumbar spine and femoral neck. To our knowledge, this study is the first to describe the frequency of reduced bone mass and associated factors in patients with childhood-onset SLE of long-term duration.
The lower bone mass observed in our patients with childhood-onset SLE is consistent with results reported in several studies of adult patients with SLE (4–6, 10, 38). Two previous studies of childhood-onset SLE (12, 13) also found lower BMD in the spine and femoral neck of patients compared with controls. The frequency of osteoporosis in the femoral neck (7%) and lumbar spine (9%) observed in our study was in the lower range as compared with the frequency reported in other studies (range 8–22%) (10, 39, 40). This might partly be explained by the younger mean age of our patients, and may also be attributable to less selection bias in favor of severely diseased patients. In southern Norway, our department represents the only pediatric rheumatology clinic, and the patients who were recruited from Rikshospitalet University Hospital presumably represent the vast majority of patients in this region in whom childhood-onset SLE was diagnosed during the given time period. Alternatively, in 2 North American studies (26, 41), higher SDI scores were reported, and based on this, a milder disease in our patient population may be another explanation. However, our patients demonstrated a relatively high frequency of osteopenia in the femoral neck (40%) and lumbar spine (41%) during the early stages of life, which is associated with a potentially higher risk of osteoporosis developing later in life.
The cumulative dose of corticosteroids was found to be an important variable in explaining decreased bone mass in the femoral neck and lumbar spine. These findings are consistent with those of several studies in adult-onset SLE (6, 8–10) and contradict the results of other studies (4, 38). Trapani et al also reported an association between the cumulative steroid dose and BMD in patients with childhood-onset SLE (13), whereas Castro et al did not observe such an association (12). The impact of corticosteroids have been a subject of controversy (19, 42, 43), but some of the differences between studies may be attributable to patient selection, study design, and different uses of corticosteroids (i.e., high-dose, low-dose, oral, intravenous). Interestingly, in our patients, corticosteroids were not identified as predictors of bone loss in the distal one-third of the radius and the total body. This probably indicates that corticosteroids have a greater impact on bone loss in areas containing greater proportions of trabecular bone (e.g., the lumbar spine), as was noted in 2 other studies (22, 43).
Male patients had lower Z scores for the lumbar spine and the total body than did female patients; additionally, in multiple regression analysis, male sex was associated with decreased bone mass. We found no differences in clinical manifestations or disease activity, severity, or duration between male and female patients, which may explain the more severe bone loss in male patients. Only a few studies have investigated bone mass in male patients with SLE, and the findings of those studies contradict ours (44, 45). However, a comparison of the results of those studies and our findings may have some limitations, in that those patients presumably did not have lower-than-expected peak bone mass during adolescence and early adulthood. Another reason that could be considered for the more severe bone loss in male patients with SLE is sex hormone abnormalities, which we did not analyze in our patients. Elevated estrogen-to-androgen ratios and hyperprolactinemia, which are associated with a potential risk of osteoporosis, have been described in male patients with SLE (45).
In randomly selected matched healthy controls, the frequency of osteopenia was low (3–7%). Based on a Gaussian distribution, we would have expected up to 16% of controls to have a Z score less than −1 SD. Despite the fact that our controls were randomly selected from the population registry, there may have been a selection bias in favor of healthier individuals, because such persons were probably more willing to participate in the BMD measurements. The mean height of controls was higher than that of patients, a finding that corroborates previous reports of growth retardation in patients with childhood-onset SLE (46). The higher mean height of the controls may have influenced and aggravated the differences between patients and controls to a certain degree, because shorter height is associated with decreased bone mass.
The higher deoxypyridinoline levels observed in young adults with SLE compared with those in controls are consistent with results reported by Teichmann et al (11). Osteocalcin levels tended to be lower in pediatric-age SLE patients than in controls, a finding reported in previous studies of children with rheumatic diseases (47) and in adults with SLE (11, 40). Reduced osteoblast function and increased bone resorption are also known to be effects of corticosteroids (21, 48, 49). However, the alteration of bone resorption and markers of bone formation has been found to be independent of corticosteroid treatment in patients with SLE (11).
A limitation of the study might be the small sample size. The ages of the SLE patients in the present study were highly variable, and for this reason, we used controls that were individually matched for age and sex, and we adjusted for age, bone area, weight, and height in all multiple linear regression analyses. The successful matching of the study population may be a strength of our study. The relatively high male-to-female ratio in our cohort was similar to that in many previous reports of childhood-onset SLE (41, 50). The reason for the higher proportion of male patients with childhood-onset SLE compared with male patients with adult-onset SLE is unknown but may be partly influenced by hormonal factors (41). The high proportion of Caucasian participants in our study may limit the generalizability of our findings to nonwhite patients with lupus.
In conclusion, we observed lower bone mass in the lumbar spine and femoral neck in patients with childhood-onset SLE compared with healthy controls, and the frequency of osteopenia was higher in patients with SLE. Decreasing BMC in the lumbar spine and femoral neck was also associated with a higher cumulative steroid dose. These results should alert clinicians to the potentially higher risk for the development of osteoporosis later in life in patients with childhood-onset SLE. For the prevention of osteoporosis, this would mean administering the lowest possible dose of corticosteroids and using corticosteroid-sparing drugs in clinical practice.