To determine the frequency of osteopenia in patients with childhood-onset systemic lupus erythematosus (SLE) compared with that in healthy matched controls, and to evaluate the relationship between disease-related variables and bone mineral mass.
Bone mineral density (BMD) and bone mineral content (BMC) were measured in a cohort of 70 patients with childhood-onset SLE (mean ± SD disease duration 10.8 ± 8.3 years, mean ± SD age 26.4 ± 9.9 years) and 70 age- and sex-matched healthy controls. BMD and BMC of the femoral neck, lumbar spine, total body, and distal one-third of the radius were measured by dual x-ray absorptiometry. We investigated the relationship between BMC and the following disease variables: cumulative dose of corticosteroids, organ damage, current use of corticosteroids, use of cyclophosphamide, age at disease onset, and disease activity at the time of diagnosis. Biochemical markers of bone metabolism were also measured.
BMD values for the lumbar spine and femoral neck were significantly lower in patients than in healthy controls. The reduction in BMD of the lumbar spine was significantly greater than that of the total body. In multiple linear regression analyses, a higher cumulative corticosteroid dose was significantly associated with lower BMC of the lumbar spine and femoral neck. Decreased lumbar spine BMC was also related to male sex.
The frequency of osteopenia was higher in patients with childhood-onset SLE than in matched controls. The lumbar spine was the most seriously affected skeletal site, followed by the femoral neck. The cumulative dose of corticosteroids was shown to be an important explanatory variable for BMC values in the lumbar spine and femoral neck.
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.
PATIENTS AND METHODS
Patients and healthy controls.
The current cross-sectional study was performed at the Department of Rheumatology, Rikshospitalet University Hospital, which serves the majority of the population of southern Norway (∼2.5 million people). The study population comprised 70 children, adolescents, and young adults with childhood-onset SLE. These subjects represent 91% of 77 patients with childhood-onset SLE who were identified by the search strategy described below. The inclusion criteria were disease onset before the age of 16 years, a minimum disease duration of 12 months, and the presence of at least 4 of the American College of Rheumatology (ACR) criteria for classification of systemic lupus erythematosus (23).
Sixty-four patients who had been admitted to Rikshospitalet University Hospital between January 1980 and June 2003 were identified from the patient register. Fifty-eight of those patients were included in the study; the other 6 patients were not enrolled (1 had a history of drug-induced lupus, 4 had died, and 1 could not participate due to severely impaired health status). Thirteen patients who had been admitted to other hospitals were identified as a result of a request to the National Register of Autoimmune Disease and questionnaires about new and previously treated patients with childhood-onset SLE that were mailed to all pediatric and rheumatology clinics in Norway. Of these patients, 12 were enrolled and 1 chose not to participate. No significant differences with respect to age, sex, disease duration, disease activity, and medication requirements were observed between patients recruited from Rikshospitalet and those recruited from other hospitals.
Healthy controls (matched for age and sex with each SLE patient) were selected randomly from the population registry of Oslo and the neighboring county of Akershus. An invitation to participate was mailed to 255 individuals, 85 of whom (33.3%) accepted. For some SLE patients, we identified 2 or more matched controls due to the different numbers of responders and nonresponders. In such cases, the first control to be examined was selected as a matched control for the patient in question.
Informed consent was obtained from the patients, controls, and the parents of patients younger than age 16 years. This study was approved by the Regional Ethics Committee for Medical Research.
Data collection and clinical measures.
All of the patients and controls were examined in accordance with a 1-day program at Rikshospitalet University Hospital, which included a clinical examination by a single physician (VL), laboratory measures, self-reported health status questionnaires, and bone mass measurements. In patients with SLE, disease activity and cumulative organ damage were measured by the SLE Disease Activity Index (SLEDAI) (24, 25) and the Systemic Lupus International Collaborating Clinics (SLICC)/ACR Damage Index (SDI) (26, 27). In addition, SLEDAI scores for the time of diagnosis were calculated retrospectively. Information on the cumulative corticosteroid dose, including pulses of methylprednisolone (expressed as prednisolone equivalents), and other reported disease variables were obtained from patients' medical records. Disease onset was defined as the time at which the initial clinical symptoms clearly attributable to SLE appeared. Disease duration was defined as the period of time from the diagnosis of SLE until the time of the study.
The erythrocyte sedimentation rate (ESR) and serum levels of albumin, ionized calcium, and parathyroid hormone (PTH) were measured by routine laboratory methods. Bone formation was assessed by measuring serum levels of osteocalcin and bone-specific alkaline phosphatase. Bone resorption was evaluated by measuring serum levels of C-terminal type I telopeptide and the urinary concentration of deoxypyridinoline.
Physical activity was quantified on a 6-point scale, where daily physical activity for 20 minutes or longer = 6, and no or very rare physical activity = 1. Physical activity in this context was defined as activity causing the subject to perspire and experience shortness of breath. Food and nutrient intake were estimated by a standardized quantitative food frequency questionnaire (28), and calculations were performed with use of the Norwegian Food Composition Table (29). Physical disability was measured by the Childhood Health Assessment Questionnaire (C-HAQ) and, for patients older than age 18 years, by the HAQ (30, 31).
Bone mass measurements.
Bone mineral mass in the femoral neck, the second through fourth lumbar vertebrae, the total body, and the distal one-third of the radius was measured with dual x-ray absorptiometry (DXA) equipment (Lunar Expert-XL; GE Lunar, Madison, WI). All analyses were performed by a single investigator using Expert-XL software version 1.91 (GE Lunar). The scanner was calibrated daily with an aluminum spine phantom, and the in vitro coefficient of variation (CV) was 0.5%. The in vivo CV (patients and healthy subjects) was 1.6% for the spine (second through fourth lumbar vertebrae) and 2% for the femoral neck. Four of our patients underwent bone mineral measurements with other DXA equipment (Lunar DPX-L; GE Lunar), which was located at the Endocrinology Department of the Rikshospitalet University Hospital. The Lunar Expert-XL (fan-beam) produces results that correlate highly with the Lunar DPX series (pencil-beam) (32, 33). Due to the presence of prosthetic joints, measurements of the total body were not obtained in 2 patients. Measurements of the distal one-third of the radius were missing in 1 patient and 1 control.
Bone mass was expressed as bone mineral density (BMD), bone mineral content (BMC), or as a Z score in terms of the number of SDs above or below the age-specific mean for healthy individuals. At present, Norwegian reference values for bone mass measurement in children and adults are not available. We therefore chose to use age- and sex-specific numerical data provided by the manufacturer (GE Lunar) to calculate Z scores for BMD using the following formula: Z score = (subject's measurement − mean measurement of the reference population)/SD of the reference population. BMD reference values for the forearm were available only for individuals ages 20 years and older. Reduced bone mass (osteopenia) was defined as a Z score less than −1 SD (34).
Bone mass was also expressed as the T score (the number of SDs above or below the mean value for young adults at the time of peak bone mass) (35), but only for patients ages 20 years and older (n = 45). This score is not applicable to children or adolescents, because they have not yet achieved peak bone mass. For the same reason, the World Health Organization definition of osteopenia (a T score between 1 and 2.5 SD below the mean value for young adults) and osteoporosis (a T score less than −2.5 SD) cannot be applied to children and adolescents (36).
Differences between patients and matched controls were tested by the paired samples t-test, Wilcoxon's test, and McNemar's test. Differences between patient groups (e.g., patients younger than age 20 years versus patients age 20 years and older) were tested by the independent sample t-test, the Mann-Whitney test, and the chi-square test. Reductions in BMD (BMD in controls – BMD in patients) at the various skeletal sites were compared using Friedman's test, with paired samples t-tests (with Bonferroni correction) as post hoc tests. Univariate and multiple linear regression analyses were used to investigate the impact of disease variables on bone mass measurements. To avoid the possibility of size-related artifacts, bone area, weight, and height were included in the multiple regression models, as proposed by Prenctice et al (37). Additional variables that are considered to be possible predictors of BMC are listed in Table 4. The variable “disease duration” was not included in regression analyses, due to high correlation with the variable “age.” The variables were entered in multiple analyses by forward variable selection methods. We thoroughly checked for possible violations from the model assumptions during analyses. P values less than or equal to 0.05 were considered significant. All statistical analyses were performed using SPSS version 12.01 software (Chicago, IL).
Table 4. Relationship between disease variables and BMC in 70 patients with childhood-onset SLE*
Distal one-third of the radius
Total body, P, univariate analysis
P, univariate analysis
Multiple linear regression analysis
P, univariate analysis
Multiple linear regression analysis
P, univariate analysis
Multiple linear regression analysis
All multiple linear regression analyses were adjusted for bone area, weight, and height. R2 values (the total explained variance of the model) were as follows: for the lumbar spine, R2 = 79%; for the femoral neck, R2 = 52%; for the distal one-third of the radius, R2 = 81%; and for total body, R2 = 90%. Beta values are nonstandardized coefficients. BMC = bone mineral content; SLE = systemic lupus erythematosus; 95% CI = 95% confidence interval; CS = corticosteroids; SDI = Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index; SLEDAI = SLE Disease Activity Index; ESR = erythrocyte sedimentation rate
Sex (female = 1, male = 2)
Age at disease onset
Cumulative CS dose
Current prednisolone user (yes = 1, no = 2)
Cyclophosphamide ever used (yes = 1, no = 2)
SLEDAI at diagnosis
ESR at diagnosis
Characteristics of the study subjects.
The study population comprised 70 patients with childhood-onset SLE and 70 healthy controls, who were individually matched for age and sex. The mean ± SD disease duration in the patients was 10.8 ± 8.3 years, and their mean ± SD age was 26.4 ± 9.9 years (range 9.8–49.3 years). Characteristics of the study groups are presented in Table 1. The patients and healthy controls were comparable with respect to body mass index, weight, daily calcium and vitamin D intake, physical activity, and smoking habits, but the mean height of the patients was significantly lower than that of controls. The patient group was more disabled physically than the healthy group, as reflected by significantly higher C-HAQ/HAQ scores in the patients.
Table 1. Characteristics of SLE patients and healthy controls*
Childhood-onset SLE (n = 70)
Healthy controls (n = 70)
Except where indicated otherwise, values are the mean ± SD. SLE = systemic lupus erythematosus; NA = not applicable; HAQ = Health Assessment Questionnaire; C-HAQ = Childhood HAQ; SLEDAI = SLE Disease Activity Index; SLICC/ACR = Systemic Lupus International Collaborative Clinics/American College of Rheumatology.
P < 0.05 versus controls.
For patients with childhood-onset SLE, n = 32; for controls, n = 24.
A comparison of female and male patients showed a similar age distribution (mean ± SD age 26.5 ± 10.0 years and 26.4 ± 9.9 years, respectively) between sexes and revealed no significant differences with regard to clinical manifestations, disease duration, age at disease onset, the SLEDAI, the SDI, or the cumulative corticosteroid dose (data not shown).
BMD in the lumbar spine and femoral neck was significantly lower in patients with childhood-onset SLE than in healthy controls; this difference was independent of the age group (age <20 years or ≥20 years) (Table 2 and Figure 1). The difference between patients and controls was also significant for total body BMD and for BMD of the distal one-third of the radius, when patients and controls were not divided into age groups (data not shown). The reduction in lumbar spine BMD (BMD in matched control – BMD in patient) was significantly greater than the reduction in total body BMD and BMD of the distal one-third of the radius, but after Bonferroni correction, this difference for the radius did not reach significance (P = 0.051).
Table 2. BMD and Z scores in children and young adults with childhood-onset SLE and age- and sex-matched healthy controls*
Except where indicated otherwise, values are the mean ± SD. Twenty-five patients were younger than age 20 years, and 45 patients were age 20 years or older. BMD = bone mineral density; SLE = systemic lupus erythematosus; NA = not available.
By paired samples t-test.
BMD in matched control − BMD in patient with childhood-onset SLE.
P < 0.01, lumbar spine versus total body, by Friedman's test, with Bonferroni correction.
Male patients had significantly lower mean Z scores for the lumbar spine and total body compared with female patients (P = 0.034 and P = 0.023, respectively). In addition, Z scores for the femoral neck tended to be nonsignificantly lower in male patients (data not shown).
Frequency of reduced bone mass.
The frequency of osteopenia (Z score less than −1 SD) was significantly higher in patients with childhood-onset SLE than in matched healthy controls for all 4 sites at which BMD was measured (Figure 2). The sites affected most frequently were the femoral neck (40% of patients versus 6% of controls) and the lumbar spine (41% of patients versus 7% of controls). When the patients were divided into 2 groups on the basis of age, a comparison between the groups showed that the frequency of reduced bone mass in patients younger than age 20 years was almost the same as that in patients ages 20 years and older (Figure 2).
Osteoporosis (T score less than −2.5 SD) was detected only in patients with childhood-onset SLE and not in any healthy controls. Furthermore, osteoporosis was observed only in the femoral neck and the lumbar spine, where the frequencies were 7% and 9%, respectively.
The level of deoxypyridinoline was significantly higher in young adult patients with SLE than in controls (Table 3). There were no statistically significant differences for other markers of bone metabolism, ionized calcium, or PTH.
Table 3. Markers of bone metabolism in patients with childhood-onset SLE and age- and sex-matched healthy controls*
Multiple linear regression analyses showed that the impact of the cumulative corticosteroid dose on the BMC was significant for the femoral neck and the lumbar spine (Table 4). In the femoral neck and lumbar spine, an increasing cumulative corticosteroid dose was associated with a decreasing BMC. In addition to the cumulative dose of corticosteroids, sex was also found to be a significant predictor of BMC in the lumbar spine, where the BMC was lower in men than in women. Although univariate analysis demonstrated that age at disease onset was highly associated with lumbar spine BMC (P < 0.001), the effect was only borderline significant (P = 0.054) after adjustment for sex and corticosteroids. No disease-related variables were identified as independent predictors of BMC in the distal one-third of the radius and the total body.
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.
We thank Gunn J. Hovland, Berit Brenden, and Gunhild A. Isaksen for conducting the DXA scans.