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Rheumatology Advance Access originally published online on November 8, 2005
Rheumatology 2006 45(1):53-60; doi:10.1093/rheumatology/kei079
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© The Author 2005. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Disease damage and low bone mineral density: an analysis of women with systemic lupus erythematosus ever and never receiving corticosteroids

C. Lee1, O. Almagor2, D. D. Dunlop2, S. Manzi4, S. Spies3, A. B. Chadha1 and R. Ramsey-Goldman1

1 Division of Rheumatology, 2 Institute for Healthcare Studies and 3 Department of Radiology, Northwestern University, Feinberg School of Medicine, Chicago, IL and 4 Department of Medicine, Division of Rheumatology and Clinical Immunology, University of Pittsburgh School of Medicine and Graduate School of Public Health, Pittsburgh, PA, USA.

Correspondence to: C. Lee, Northwestern University, Feinberg School of Medicine, Division of Rheumatology, 240 E. Huron Street, McGaw Pavilion #2300, Chicago, IL 60611, USA. E-mail: c-lee17{at}northwestern.edu


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Objectives. To evaluate the relationship between disease damage and bone mineral density (BMD) in women with systemic lupus erythematosus (SLE).

Methods. A cross-sectional study was conducted among 307 women with SLE. Patients attended a single clinic visit that included an interview, physical examination, laboratory testing and BMD measurements (hip and/or lumbar spine). Women were stratified by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology cumulative disease damage index (SDI) ≥1 (Damage) vs SDI=0 (No Damage), and prior use of corticosteroids (CS), yielding four groups: (1) Damage/CS+ (n=138), (2) Damage/CS– (n=23), (3) no Damage/CS– (n=100), and (4) no Damage/CS– (n=46).

Results. Mean age at SLE diagnosis was 32.7 ± 11.8 yr, 24.4% were African American, 65.0% were premenopausal, and mean SDI ± S.D. was 1.3 ± 1.8. In the unadjusted and adjusted models controlling for significant univariate risk factors for osteoporosis, the reference group (Group 1) had significantly lower mean BMD T-scores at the hip and lumbar spine than groups having no disease damage (Groups 3 and 4) independent of CS use status. Similar hip and lumbar spine mean BMD T-scores were observed in women with disease damage with and without CS exposure (Groups 1 and 2).

Conclusions. Women with SLE having disease damage and no CS use had BMD T-scores at the hip and lumbar spine similar to those of women with disease damage and prior CS use. These findings suggest an association between disease damage and lower BMD T-scores in women with SLE.

KEY WORDS: SLE, Bone mineral density, Osteoporosis, Disease damage, Corticosteroids


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Although the incidence of systemic lupus erythematosus (SLE) has increased, disease mortality has improved in some, but not all, SLE populations [1]. Accordingly, there is greater attention to preventing SLE related comorbidities [2–8]. An important and potentially preventable disease-related comorbidity among SLE patients is osteoporosis [9]. The aetiology of bone loss in SLE is probably multifactorial, involving both disease- and non-disease-related factors. The contribution of corticosteroid therapy to bone loss in SLE remains unclear as several studies have reported reduced bone mineral density (BMD) associated with corticosteroid use in SLE patients [10–19] while others have found no association [20–22]. Furthermore, some investigators have reported a relationship between SLE and lower BMD in patients never receiving corticosteroids [21, 23], suggesting that SLE per se may be a risk factor for bone loss. Inflammatory mediators such as interleukin (IL)-6, IL-1 and tumour necrosis factor-{alpha} can promote bone resorption [24–26]; thus, there may be a physiological basis for SLE serving as a contributing risk factor for lower BMD in lupus patients independent of corticosteroid use [21, 23, 27].

Disease damage in SLE is reflective of disease severity over time and may be associated with bone loss in the lupus population [28]. However, a relatively limited number of studies have examined whether disease damage in SLE is related to lower BMD [11–13, 15]. These studies have either exclusively included SLE patients with corticosteroid exposure or have failed to find any link between disease damage and reduced BMD after adjusting for age, body mass index (BMI), corticosteroid use and other SLE-related variables, including disease duration. Since corticosteroids may contribute to BMD reduction, a more direct approach to exploring the potential association between disease damage and low BMD is made by assessing SLE patients without prior corticosteroid use. We performed a post hoc analysis of data collected to study bone health in African American and Caucasian women with SLE to investigate whether disease damage is associated with lower BMD in women with SLE who have ever and never received corticosteroids.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Study population and data collection
A total of 307 women with SLE were recruited from the Chicago Lupus Database and Pittsburgh Lupus Registry conducted from 1996 to 2002 for this cross-sectional study. All women met at least three American College of Rheumatology (ACR) criteria for SLE [29, 30] and had clinical definition of SLE. Participants attended a single clinic visit that included an interview, physical examination, laboratory testing and BMD measurements. Institutional review boards at both study centres approved the protocol for this study, and all participants provided informed written consent prior to participation.

We collected information on age (age at SLE diagnosis and age at menopause), race (African American or Caucasian) and SLE disease duration, available from the Chicago Lupus Database and the Pittsburgh Lupus Registry. Women also provided information on clinically relevant variables of osteoporosis by completing self-administered questionnaires, which included information on corticosteroid use, defined as ‘ever’ or ‘never’ receiving corticosteroids; body mass index (BMI) in kg/m2; reported daily caffeine and alcohol use; daily calcium and/or vitamin D consumption from diet and supplements; any prior use of medication(s) for osteoporosis, including etidronate, alendronate and calcitonin; current smoking status; comorbid conditions (hypothyroidism, diabetes, renal disease), postmenopausal status; and any fractures since SLE diagnosis. Renal disease as a comorbid condition was defined as SLE-related renal manifestations (e.g. proteinuria >0.5 g or 3+ protein; or cellular casts; or positive renal biopsy), but not necessarily meeting the Systemic Lupus International Collaborating Clinics/American College of Rheumatology cumulative disease damage index (SDI) definition of renal damage. When completing the questionnaire item on past and/or current corticosteroid use, we requested information on the type, dose and duration of corticosteroid medication used, the estimated average cumulative daily dose of corticosteroids, median current dose of corticosteroid in mg per day, and duration of corticosteroid use longer than 1 yr. We used an arbitrary cutoff for the average cumulative daily dose of corticosteroid use, and we determined age at study visit using the date of study visit obtained from the self-administered questionnaire and date of birth available from the SLE databases. Renal involvement was defined using the 1982 ACR SLE classification criteria [29].

Disease damage was scored using the SDI, a validated measure of damage occurring in the SLE disease course regardless of cause, modified by excluding the osteoporosis/fracture item (1 point) from a possible maximum score of 46 [31]. Women with SLE were grouped by their cumulative disease damage index as either having damage (SDI ≥1) or having no damage (SDI = 0). They were further stratified according to any prior use of corticosteroids: ever receiving corticosteroid (CS+) and never receiving corticosteroid (CS–) to yield four groups: Group 1, Damage/CS+ (n = 138); Group 2, Damage/CS– (n = 23); Group 3, No Damage/CS+ (n = 100); and Group 4, No Damage/CS– (n = 46). Group 1 served as the reference group to which all other groups were compared. Selection of the reference group was made a priori on the basis that those SLE patients having both disease damage and ever receiving corticosteroid may be expected to have the lowest BMD T-scores of any group.

In addition to disease damage, we evaluated the relationship between BMD T-scores and disease activity using a pilot version of the validated Systemic Lupus Activity Questionnaire (SLAQ), previously referred to as the Self-Assessed Systemic Lupus Activity Measure (SA-SLAM). The SA-SLAM and SLAQ were based on the Systemic Lupus Activity Measure (SLAM) and include a single Patient Global Assessment concerning presence and severity of lupus activity, and 24 questions related to specific disease symptoms present over the past 1 month, as previously described [32].

Bone density measurements
BMD was measured by dual energy X-ray absorptiometry using a Hologic QDR-4500 densitometer (Hologic, Waltham, MA, USA) in Chicago and a Hologic QDR-2000 densitometer in Pittsburgh. Measurements were made at the hip (n = 298) and/or lumbar spine (n = 303). All BMD results were expressed as g/cm2 or BMD T-scores. The lumbar spine was measured from L1 to L4, and the mean lumbar spine BMD T-scores result were reported. For the hip, the total hip BMD T-scores were reported. Based on the World Health Organization (WHO) criteria for osteoporosis, subjects were determined to have BMD T-scores classified as normal (T-score ≥1.0), osteopenic (T-score between –1.0 and –2.5) or osteoporotic (T-score ≤2.5) [33].

To assess intra- and inter-instrument variations of the two densitometers, we measured lumbar spine and femur phantoms on machines at both the Chicago and Pittsburgh study centres. Block phantoms of standardized densities were performed daily to test variation in system linearity. The intra-instrument coefficients of variation were less than 0.56% for the lumbar spine, 0.46% for the femur, and 0.44% for the block phantoms. The lumbar spine phantom measurement was 4% higher with the QDR-2000 compared with the QDR-4500 model. Since the intra-instrument variation was similar throughout the observation interval (1996–2002), a 4% correction factor was applied to the lumbar spine measurement obtained in women from the Pittsburgh Lupus Registry. Data analyses were performed using both the corrected and uncorrected lumbar spine measurements. There were no differences in results; therefore, only the corrected lumbar spine results are shown.

Data analysis
The hip and lumbar spine BMD T-scores of the reference group, Group 1 (Damage/CS+), were compared with those for Groups 2–4 using unadjusted and adjusted multiple linear regression analysis that included data from all women. To validly account for multiple comparisons of BMD T-scores for Group 1 vs Groups 2–4, Dunnett's t-test was applied to maintain an {alpha} = 0.05 family-wise error rate [34]. In the adjusted analysis, we compared BMD T-scores of Group 1 with those for Groups 2–4 using Dunnett's t-test controlling for significant osteoporosis risk factors identified from univariate screening of clinically relevant variables of osteoporosis. Adjusted mean hip and lumbar spine BMD T-scores were determined using a multiple linear regression model that included dichotomized variables representing Groups 2–4 (Group 1 serving as the reference), variables identified from risk factor screening, study centre, which was a study design factor, and SLAQ. In a two-stage risk factor screening, we first selected clinically relevant variables of osteoporosis using univariate linear regression. The second stage evaluated significant univariate risk factors for potential collinearity; among correlated risk factors, those most strongly related to a lower BMD T-score were chosen. For strongly correlated risk factors, a sensitivity analysis exchanging alternative univariate risk factors with its correlate in the multiple regression model was also performed (data not shown). A nominal {alpha} = 0.05 level was used for all statistical testing. An associated 95% confidence interval (CI) that excludes zero denotes a statistically significant difference. Statistical calculations were completed using SAS® 9 (SAS Institute, Cary, NC, USA).


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Most of the 307 women participating in the study were Caucasian and premenopausal, and had had SLE for more than 5 yr, but the mean SDI for all women was relatively low, as shown in Table 1. Among 233 of the 238 SLE women ever receiving corticosteroids providing information on the length of their corticosteroid use, mean duration of corticosteroid use ± S.D. was 6.5 ± 7.1 yr with a median daily dose of 5 mg (range 0–60 mg/day). In addition, 155 of the 238 (65.1%) women ever receiving corticosteroids reported currently taking corticosteroids, while 31 (10.0%) of all women had ever taken medication(s) for osteoporosis. The mean BMD T-scores ± S.D. for the women were –0.530 ± 1.1 g/cm2 at the hip and –0.675 ± 1.3 g/cm2 at the lumbar spine. The frequency of osteopenia at the hip (27.5%) and lumbar spine (33.0%) was higher than the frequency of osteoporosis at these sites (hip 5.0%, lumbar spine 6.9%, respectively).


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  		TABLE 1. Demographics and clinical characteristics of women with SLE (n = 307)

 
Clinically relevant variables of osteoporosis, which we screened in our univariate analysis, characterizing women as stratified according to their SDI and status of prior corticosteroid use are shown in Table 2. Group 1 (Damage/CS+) included the largest number of women (n = 138) and had similar mean age at SLE diagnosis to Group 3 (No Damage/CS+), but was comparatively younger than Groups 2 (Damage/CS–) and 4 (No Damage/CS–). Women in Group 1 were older at study visit than those in Groups 3 and 4, but their mean age at menopause was comparable to the other three groups. The BMI for Group 1 was similar to Groups 2 and 4, but higher than Group 3. Additionally, women in Group 1 had the longest disease duration and highest SDI score of any group. In terms of disease activity as measured by the SLAQ, Groups 1 and 2 had higher mean SLAQ scores compared with Groups 3 and 4. Furthermore, Group 1 had the highest proportion of postmenopausal women, African Americans, and women with disease duration of more than 5 yr. With respect to fractures since SLE diagnosis, Group 1 had the largest proportion of women reporting fractures. Group 1 also had the greatest proportion of women who had ever taken any medication(s) for osteoporosis, while no women in Group 4 reported use of such medications.


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  		TABLE 2. Characteristics of women with SLE stratified by Systemic Lupus International Collaborating Clinics/American College of Rheumatology cumulative disease damage index (SDI) and prior corticosteroid (CS) use

 
With regard to lifestyle variables, the highest proportion of women reporting daily calcium intake between 800 and 2000 mg per day and daily vitamin D intake ≥400 IU belonged to the two groups who had ever used corticosteroids (Groups 1 and 3). Among all four groups, Group 1 had the lowest proportion of women reporting any alcohol intake and who were currently smoking, but did not differ from the other groups in the proportion of women reporting any daily caffeine use. For comorbid conditions, the highest proportion of women with renal disease belonged to Group 1, and the proportions of women having diabetes and hypothyroidism for each group are shown in Table 2.

Among women who ever used corticosteroids, similar proportions of women in Group 1 (68.1%) and Group 3 (61.2%) were currently taking corticosteroids. The two groups were comparable in their current daily dose of corticosteroid [Group 1, mean dose of 7.7 ± 9.1 mg/day and median dose of 5 mg/day (range 0–60 mg/day) vs Group 3, mean dose of 8.7 ± 11.2 mg/day and median dose of 5 mg/day (range 0–50 mg/day)], as well as in the proportions of women reporting an average cumulative dose of corticosteroids greater than 7.5 mg/day (Group 1, 74.4% vs Group 3, 79.1%). Groups 1 and 3 were also similar in their mean duration of corticosteroid use of more than 1 yr (Group 1, 85.8% vs Group 3, 72.7%). Women in Group 1 had longer mean duration of corticosteroid use than Group 3 (Group 1, 9.1 ± 8.1 yr vs Group 3, 3.2 ± 3.9 yr), but this was not surprising since disease duration in Group 1 was almost twice as long as in Group 3.

Prior to adjusting for significant univariate risk factors for osteoporosis, BMD T-scores at the hip and lumbar spine tended to be lower for women with disease damage (Groups 1 and 2) relative to women with no damage (Groups 3 and 4), as represented in Fig. 1. Moreover, mean BMD T-scores at the hip and lumbar spine were significantly lower for women in Group 1 compared with those in Groups 3 and 4. In contrast, women in Group 2 had similarly low BMD T-scores at both anatomical sites compared with Group 1. The values for the measured differences in mean BMD T-scores for Groups 2, 3 and 4 compared with Group 1 are presented in Table 3.



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  		FIG. 1. Unadjusted mean bone mineral density (BMD) T-scores ± S.E.M. at the hip and lumbar spine for SLE women stratified according to disease damage (SDI) and corticosteroid (CS) use status: CS+ (ever receiving corticosteroids) and CS– (never receiving corticosteroids). *P<0.05 based on Dunnett's test for multiple comparisons with the referent group (Group 1). SDI, Systemic Lupus International Collaborating Clinics/American College of Rheumatology cumulative disease damage index.

 

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  		TABLE 3. Differences in mean bone mineral density (BMD) T-score values for Groups 2, 3 and 4 compared with the reference group

 
The BMD T-scores for Groups 2, 3 and 4 were also compared with Group 1 in a multiple linear regression model after adjusting for significant univariate risk factors for osteoporosis identified from screening of clinically relevant variables of osteoporosis. Significant univariate risk factors included age at study visit, African American race, BMI, disease duration, caffeine use and hypothyroidism. Two significant univariate risk factors of osteoporosis were excluded from the adjusted multiple regression model to avoid multicollinearity as they had significant correlation with other risk factors. Excluded risk factors were age at menopause (correlated with age at study visit), and any fractures (correlated with age at study and disease duration). A sensitivity analysis exchanging alternative univariate risk factors (e.g. age at menopause) with its correlate(s) (e.g. age at study visit) showed comparable results in the multiple linear regression model (data not shown). The SLAQ, which was also included in the multiple regression model, was not significantly associated with changes in BMD T-scores at either the hip (P = 0.88) or lumbar spine (P = 0.44) in the univariate linear regression analysis.

The findings from the adjusted analysis were similar to the unadjusted results. The mean BMD T-scores at the hip and lumbar spine for Group 1 were statistically lower compared with Groups 3 and 4, and no significant differences in mean BMD T-scores were found between Groups 1 and 2, as seen in Fig. 2. As was the case for the unadjusted results, the trend for lower BMD T-scores in the two groups with disease damage persisted. The measured differences in BMD T-scores for Groups 2, 3 and 4 compared with Group 1 for the hip and lumbar spine are summarized in Table 2.



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  		FIG. 2. Adjusted mean bone mineral density (BMD) T-scores ± S.E.M. at the hip and lumbar spine for SLE women stratified according to disease damage (SDI) and corticosteroid (CS) use status: CS+ (ever receiving corticosteroids) and CS– (never receiving corticosteroids). *P<0.05 based on Dunnett's test for multiple comparisons with the referent group (Group 1). Multiple linear regression model was adjusted for the following significant univariate risk factors for osteoporosis: age at study visit, African American race, body mass index, disease duration, caffeine use, have hypothyroidism, and any prior use of medication(s) for osteoporosis (etidronate, alendronate, calcitonin). The study site (Chicago or Pittsburgh) was included in the model as it was a study design variable, and the Systemic Lupus Activity Questionnaire (SLAQ) was also included to control for disease activity. SDI, Systemic Lupus International Collaborating Clinics/American College of Rheumatology cumulative disease damage index.

 
We examined the conditions contributing to the SDI score for women in Group 2 in order to explore why patients having disease damage did not also receive treatment with corticosteroids. The most common categories of disease damage contributing to the SDI ≥1 for women in Group 2 included cutaneous, musculoskeletal, malignancy, major psychosis, and angina or prior coronary artery bypass grafting. Rare events included retinal change or optic atrophy, premature gonadal failure, pleural fibrosis, pericarditis for 6 months, or pericardiectomy, myocardial infarct ever, and end-stage renal disease. With the possible exception of one case of pericarditis for 6 months or pericardiectomy, which could have been either a SLE- or a non-SLE-related complication, the remaining individual SDI items contributing to an elevated disease damage score consisted of conditions that could have been managed without using corticosteroids. Women in Group 1 experienced all the categories of cumulative disease damage that were observed in Group 2. However, Group 1 sustained additional disease damage not seen in Group 2, including erosive arthritis, venous thrombosis, seizures, cerebral vascular accidents, proteinuria, renal insufficiency, neuropathy, transverse myelitis, cardiomyopathy and valvular disease, many of which probably required treatment with corticosteroids. Not surprisingly, disease damage items probably related to corticosteroid use, including cataracts and avascular necrosis, were more common in Group 1 than in Group 2. Despite Groups 1 and 2 each having an overall SDI ≥1, examination of the individual disease damage components contributing to the SDI provides some insight into why one group, but not the other, received corticosteroids.


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
In this study of women with SLE, we found significantly reduced BMD T-scores at both the hip and lumbar spine in those having disease damage and ever receiving corticosteroids (Group 1) compared with women without disease damage (Groups 3 and 4), but similar to those with damage and no corticosteroid exposure (Group 2). These observations are noteworthy given the overall corticosteroid burden and the potential for corticosteroid induced bone loss in Group 1, which is in direct contrast to the absence of corticosteroid exposure in Group 2. We observed a similarly strong relationship between the presence of disease damage and lower BMD at both the lumbar spine and hip even after adjusting for more than several significant univariate risk factors for osteoporosis in our multiple linear regression analysis. These results support our hypothesis that there is an inverse association between disease damage and BMD in women with SLE independent of corticosteroid use. However, our findings do not discount the possible effects corticosteroids may have had on BMD. For instance, among women without disease damage (Groups 3 and 4), those ever receiving corticosteroids demonstrated slightly lower, albeit not statistically different, BMD T-scores at the hip and lumbar spine relative to women never receiving corticosteroids.

Whereas disease damage appeared to be associated with lower BMD, disease activity as measured by SLAQ was not significantly related to lower BMD T-scores in our univariate linear regression analysis. While women with disease damage also tended to have higher disease activity, the latter probably reflects disease status at one point in time rather than chronic and irreversible clinical conditions, which are better represented by disease damage. Such inherent limitation of disease activity may in part explain the absence of any significant association between disease activity and BMD T-scores in our study.

While a greater proportion of women with SLE who had disease damage (Groups 1 and 2) were postmenopausal, menopause status strongly correlated with mean age at study visit, and we adjusted for this age variable in our multiple linear regression model. Thus, the lower BMD T-scores at both the hip and lumbar spine in SLE women with disease damage are unlikely to be explained exclusively by either age or menopausal status. As might be expected, the group with the highest number of symptomatic fractures (Group 1) was also the group with the largest proportion of women reporting prior use of medication(s) for osteoporosis. Data were unavailable on the compliance and/or duration of use of these bone-protective agents by women in this study. Nonetheless, use of osteoporosis therapies by women in Group 1 could have potentially preserved or even increased their BMD levels, leading to BMD T-scores similar to those of women in Group 2. However, we accounted for prior use of osteoporosis medications in our analysis, which reduces the likelihood that use of such bone-protective agents significantly contributed to the similar BMD T-scores found between Groups 1 and 2.

Few studies have examined the relationship between either disease activity or damage and BMD in SLE. In the case of disease activity, Petri and colleagues reported that active SLE, as measured by a low serum C4 level, was an independent predictor of lower BMD in the lumbar spine [35]. However, Dhillon and colleagues found no association between disease activity and lumbar BMD, as measured by British Isles Lupus Assessment Group (BILAG) score, in 10 premenopausal SLE women without prior corticosteroid use despite more active disease [20]. Yet the small number of patients in their study limited the ability to detect a significant association between BMD and disease activity in SLE groups with and without corticosteroid use. In a prospective study examining consecutive measurements of BMD in 37 SLE patients, Hansen and colleagues found no correlation between disease activity and BMD, as measured by the SLE Disease Activity Index (SLEDAI), either at baseline or follow-up at 1 and 2 yr [14]. But as was the case in the study by Dhillon, as well as in other similar investigations [15, 22], the relatively modest size of the studies may have precluded detection of any significant relationship between disease activity and bone loss. Our findings on the relation between disease activity and BMD are consistent with prior reports, but based on a larger number of women.

On the other hand, the relationship between disease damage and bone loss has been reported in other rheumatic diseases, such as rheumatoid arthritis, yet there is a relative dearth of investigative data on the relationship between disease damage and bone loss in SLE [28, 36, 37]. Sinigaglia and colleagues [11] reported an association between higher SDI levels and lower BMD at the hip and lumbar spine in SLE women with osteoporosis compared with age-matched controls. However, all patients in the Sinigaglia study were currently taking or had previously received corticosteroids. Additionally, among individuals with elevated SDI scores and lower BMD, higher cumulative corticosteroid use appeared to be an important contributor to reduced BMD. In another study, Kipen and colleagues [12] reported a significant reduction in BMD at the lumbar spine and femoral neck in SLE patients with higher SDI scores in an univariate analysis. But the authors found no association between SDI (1 vs 0 or >1 vs 0) and reduced BMD at either the lumbar spine or femoral neck after adjusting for age, BMI, corticosteroid use, SLE duration and disease activity. Likewise, Kipen and colleagues subsequently found no relationship between BMD and SDI in a 3-yr follow-up study of SLE women [13]. In both Kipen studies, heterogeneity of the studied SLE population alone or due to their relatively mild disease, in part reflected by the low SDI scores and a low prevalence of significant renal disease, could explain why no association was seen between SDI and low BMD [12, 13]. In contrast, Pineau and colleagues reported disease damage as an independent predictor of lower bone mass. In their study, the average cumulative disease damage as measured by the SDI, with exclusion of the osteoporosis/fracture item from the total score as we did, was 2.51 in women with osteoporosis, which was comparable to the figure for women in the referent group of our study [28]. Moreover, the authors found no significant association between corticosteroids and lower BMD, a finding supported by our observations based on larger number of women.

SLE is a prototypical autoimmune inflammatory condition in which cumulative disease damage, as represented by the SDI, reflects organ injury that may be a consequence of persistent or repeated episodes of disease activity. Levels of inflammatory cytokines, such as interferon (IFN)-{gamma}, interleukin (IL)-18, IL-6 and possibly IL-1, are increased in SLE [38, 39]. IL-1 and IL-6 are key stimulators of receptor activator of nuclear factor-{kappa}B ligand (RANKL), a member of the tumour necrosis factor-{alpha} superfamily involved in osteoclastogenesis. RANKL exerts its effect by binding to RANK, which is located on surfaces of osteoclasts and their precursors. Interaction between RANKL and RANK results in osteoclastic differentiation and activation necessary for bone resorption [40]. The RANKL and RANK system appears to have a role in bone loss in other inflammatory autoimmune disorders, including rheumatoid arthritis and inflammatory bowel disease [41, 42]. Although speculative, the inflammatory milieu that characterizes SLE may create a bone microenvironment, in part via RANK/RANKL activity, promoting greater bone resorption than formation, resulting in net bone loss. Such an explanation might account for the similarly reduced BMD levels observed for the two groups with disease damage (e.g. SDI ≥1), despite the absence of corticosteroid exposure in one of these groups.

Given the relatively ubiquitous use of corticosteroids in the treatment of SLE, the strength of the current study is that it offers comparative data from corticosteroid-naive SLE patients, which allows a more direct means of assessing the potential effect of disease damage on BMD. Also, the overall number of participants included in this study represents one of the largest groups of SLE women undergoing BMD assessment. Yet the two groups of SLE women never receiving corticosteroid (Groups 2 and 4) were smaller than the groups ever receiving corticosteroids (Groups 1 and 3), and the possibility of a type II error exists. Even so, our smaller groups are comparable to the total size of SLE groups in some previously published studies examining the issue of disease damage and BMD. Furthermore, the a priori selection of our reference group, also the largest of the four groups, allowed us to show significant differences in BMD T-scores even after controlling for multiple risk factors for osteoporosis. The availability and inclusion of larger and more comparable numbers of SLE women in all four groups may have allowed us to better discern the impact of disease damage on BMD. In addition, stratification of women into the four groups was in part dependent on patients’ reported use of corticosteroids. While we cannot completely exclude the possibility of misclassification of some individuals with respect to their corticosteroid use status, we requested information on the type, amount and duration of corticosteroid usage from all women. By collecting this additional and more specific information regarding corticosteroid use, the chances of misclassification are probably minimized. Despite long-standing SLE in many of the participants, overall severity of disease damage for our study group, which consisted exclusively of women, was relatively low, and only a very small number of individuals used osteoporosis therapies. Based on our results, we might expect women with greater disease damage to have lower bone density. However, our findings may not be generalizable to all SLE patients having disease damage, including male patients, as well as those on medications to prevent or treat osteoporosis. Lastly, the cross-sectional nature of our study does not allow us to examine the predictive value of SDI for future BMD status, which may warrant further investigation.

In summary, disease damage in SLE patients may itself be a potential risk factor associated with lower BMD. In the context of prior or continued corticosteroid exposure, any association of SLE-related damage and diminished BMD may be less distinct. By stratifying study participants according to disease damage and corticosteroid use status, our findings suggest a relationship between the presence of disease damage and lower BMD, one that is independent of corticosteroid use. This relationship may be better defined in future prospective studies, particularly those including corticosteroid-naive SLE populations.


   Acknowledgments
 
We are indebted to Emily Wolf for her technical and editorial assistance in the preparation of this manuscript.

This research was supported by grants from the National Institutes of Health T32-AR07611 and K12-RR017707 (C.L.); K24-AR02213, RO1-AR4676402, RO1-HL074335, RO1-AR46588, NCRR/GCRC MO1-RR00056, AR02213, The Lupus Foundation of Pennsylvania (S.M.); K24-AR02318, P60-AR30692, P60-AR48098, NCRR/GCRC M01-RR00048, Arthritis Foundation Clinical Science Grant, The Lupus Foundation of Illinois, The Arthritis Foundation Greater Chicago Chapter, and unrestricted educational and research grants from Proctor and Gamble Pharmaceuticals and Merck (R.R.-G.). The other authors have declared no conflicts of interest.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Submitted 7 July 2005; revised version accepted 14 July 2005.
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K. Almehed, H. Forsblad d'Elia, G. Kvist, C. Ohlsson, and H. Carlsten
Prevalence and risk factors of osteoporosis in female SLE patients--extended report
Rheumatology, July 1, 2007; 46(7): 1185 - 1190.
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