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Rheumatology Advance Access published online on May 11, 2007
Rheumatology, doi:10.1093/rheumatology/kem105
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© The Author 2007. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Prevalence and risk factors of osteoporosis in female SLE patients—extended report

K. Almehed, H. Forsblad d’Elia, G. Kvist1, C. Ohlsson2 and H. Carlsten

Department of Rheumatology and Inflammation Reserch, Sahlgrenska Academy at Göteborg University, 1Department of Rheumatology, Borås and 2Department of Internal Medicine, Sahlgrenska Academy at Göteborg University, Sweden

Correspondence to: K. Almehed Department of Rheumatology and Inflammation Research, Guldhedsgatan 10, S-413 46 Göteborg, Sweden. E-mail: katarina.almehed{at}vgregion.se


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Ethical aspects
 Results
 Discussion
 Acknowledgements
 References
 
Objectives. To determine the frequency of osteoporosis and possible risk factors of low bone mineral density (BMD) in women with systemic lupus erythematous (SLE) in western Sweden. In addition, to evaluate if adequate anti-osteoporotic treatment was provided.

Methods. BMD was measured at radius, lumbar spine and hip by dual X-ray absorptiometry (DXA). An ‘expected’ control BMD was calculated for each patient. Simple and multiple linear regression analyses were performed to determine associations between BMD and demographic and disease-related variables.

Results. One hundred and sixty-three women were included. Median age was 47 (20–82) yrs, 89 (55%) were post-menopausal and 85 (52%) were taking glucocorticosteroids. BMD was significantly reduced in all measured sites compared with expected BMD. Thirty-seven (23%), 18 (11%) and 6 (4%) of the patients were osteoporotic in at least one, two and three or more measured locations. Bisphosphonates were used by 23 (27%) of patients taking glucocorticosteroids and 13 (35%) with osteoporosis. High age and low weight or BMI were associated with low BMD in all measured sites. In total hip, high SLICC/American Collage of Rheumatology (ACR), ESR and ‘combinations of DMARD’ were additional markers of low BMD. High S-creatinine was associated with low BMD in lumbal spine whereas high S-creatinine and CRP were markers in radius.

Conclusion. Women with SLE are at greater risk of osteoporosis compared with controls and few are treated adequately. Factors associated with low BMD in SLE are high age and low weight but also markers of inflammation, impaired kidney function and disease damage, however glucocorticosteroids were not associated.

KEY WORDS: Systemic lupus erythematosus, Osteoporosis, Bone mineral density, Glucocorticosteroids, Cross-sectional study, Risk factors


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Ethical aspects
 Results
 Discussion
 Acknowledgements
 References
 
Systemic lupus erythematosus (SLE) is a disease full of nuances. As the treatment of SLE has been more effective the focus has partly shifted from main concern of short-term morbidity and survival to possible long-term problems and medication side effects such as osteoporosis. Swedish women are known to have a high prevalence of osteoporosis and osteoporotic fractures [1]. Fractures can lead to increased morbidity and mortality [2, 3]. Women with SLE are, in addition, directly or indirectly exposed to factors that can induce bone loss. For example, many of the patients are treated with glucocorticosteroids and have lower age of menopause due to the disease itself or its treatment with cytotoxic substances [4]. Treatment with hormone replacement therapy (HRT) is controversial since it may induce SLE flares [5]. Low dietary intake of calcium and vitamin D combined with avoidance of sun light can contribute to deficiency of vitamin D necessary for the bone metabolism [6]. Interactions between proinflammatory cytokines and bone cells may play an important role in diseases with systemic inflammation like SLE. Studies from different parts of the world have shown a lower bone mineral density (BMD) in SLE patients than in the healthy population [7–10] and equal to patients with rheumatoid arthritis [11]. The aim of this study was to investigate the prevalence of osteoporosis in a Swedish cohort of SLE patients and to find out if the participants are given adequate anti-osteoporotic medication. We also wanted to look for markers, or risk factors, of low BMD in this population.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Ethical aspects
 Results
 Discussion
 Acknowledgements
 References
 
Patients
All patients with SLE attending the rheumatology clinics in Göteborg and Borås, in western Sweden, were identified from administrative registers. Three hundred and thirty-nine patients, male and female, were identified and invited by mail to participate in this observational, cross-sectional study. As shown in Fig. 1, the reply frequency was 69% (234/339) and 60% (204/339) of patients were willing to enter the trial. Thirty patients were not able to participate for the following reasons: six felt too tired or too ill, two were going to move to other parts of Sweden during the study, one patient died between invitation and examination and twenty-one patients just did not want to participate, giving no specific reason. At the first visit, 16 patients out of 204 did not fulfil at least four of the 1982 ACR classification criteria for SLE [12] and were therefore excluded. Two patients were excluded because of pregnancy and four patients did not complete the examinations. A total of 182 patients, 163 women and 19 men, completed the survey. Since only 19 male patients were enrolled they were excluded in the analyses. Participants attended three visits to the clinic during the winter and spring 2002–2003. At the first clinic visit physical examination, interview and questionnaires were obtained. At the second clinic visit blood samples and urine samples were obtained and the third visit included dual X-ray absorptiometry (DXA) measurements. For each patient, data were recorded on age, duration of disease, weight and height. Medication, intake of cheese and milk, smoking habits, physical activity and menopausal status were assessed by self administered questionnaires. disease-modifying anti-rheumatic drug (DMARD) medication was recorded as either a single treatment or combinations of two or three DMARDs. Dietary calcium intake was calculated from information on average intake of cheese and milk. Exercise was recorded as ‘times per week with regular physical exercise’ and it is therefore possible to get a median value of zero.


Figure 1
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  		FIG. 1. Procedure of enrolment to study and reasons for discontinuation.

 
Cumulative corticosteroid intake was calculated as thoroughly as possible by reading all patients’ medical records. Disease activity was scored by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI-2K) [13] and disease damage was recorded according to Systemic Lupus International Collaborative Clinics (SLICC/ACR) [14]. The same rheumatologist assessed all patients (K.A.).

Venous blood samples including ESR, CRP, haemoglobin concentration, creatinine and ionized calcium, were obtained in the morning after an overnight fast and were measured using standard laboratory techniques.

BMD measurements
Lumbar spine (L2-L4), non-dominant hip (femoral neck and total hip) and non-dominant distal forearm (the diaphysal 33% of radius and total radius) were measured by DXA. It was not possible to evaluate BMD in every patient at all skeletal sites according to hip replacement and osteosynthetic material at measured sites. Three different patients have at least one missing BMD value. The same equipment was used for all measurements, Lunar Prodigy densitometer, 12165 (GE Medical Systems). All measurements were performed in accordance with standard instrument procedures and matched to gender, race and weight. The precisions for duplicate measurements were 0.9% for lumbar spine, 0.5% for left total hip and femoral neck and 2.8% for radius. All BMD results were expressed in absolute values (g/cm2) and as the number of standard deviations (S.D) above or below the mean results of young female adults, T-score, as well as compared with an age matched female reference population, Z-score. Osteoporosis was defined according to World Health Organization (WHO) as a BMD value at or below –2.5 S.D., and osteopenia between –1 and –2.5 S.D., compared with the young adult mean value measured at any site using DXA [15].

Reference population
GE Healthcare provided data of the reference population and the equations for Z-score estimations from the Lunar Progidy (12165) software. These adjust the BMD values for age and weight. The equations are derived by the manufacturer from BMD reference data collected from a pooled North European/United States population of ~12 000 healthy women aged 20–80 [16]. Equations were used to calculate an expected BMD value for each patient by adding age (yr) and weight (kg).
Femur total for ages
    20–45 1.00 – [0.001 x (age – 30)] + [0.003 x (weight – 65)]
    46–65 0.985 – [0.006 x (age – 45)] + [0.003 x (weight – 65)]
    66–100 0.865 – [0.0055 x (age – 65)] + [0.003 x (weight – 65)]
Femur neck for ages
    20–45 0.98 – [0.002 x (age – 30)] + [0.003 x (weight – 65)]
    46–65 0.95 – [0.007 x (age – 45)] + [0.003 x (weight – 65)]
    66–100 0.81 – [0.004 x (age – 65)] + [0.003 x (weight – 65)]
Spine L2-L4 for ages
    20–45 1.20 – [0.000 x (age – 30)] + [0.004 x (weight – 65)]
    46–65 1.20 – [0.0095 x (age – 45)] + [0.004 x (weight – 65)]
    66-100 0.98 – [0.002 x (age – 65)] + [0.004 x (weight – 65)]
Distal radius 33% for ages
    20–50 0.8875 – [0.000 x (age – 30)] + [0.00 x (weight – 65)]
    51–100 0.8875 – [0.008 x (age – 50)] + [0.00 x (weight – 65)]

This ‘expected’ BMD value was compared to the observed BMD values measured with DXA. A measured BMD value beneath the ‘expected’ BMD refers to the patient having a bone mass lower than expected.


   Ethical aspects
Top
 Abstract
 Introduction
 Materials and methods
 Ethical aspects
Results
 Discussion
 Acknowledgements
 References
 
All patients gave informed written consent prior to participation and the study was approved of by the Ethics Committee at Sahlgrenska Academy at the University of Göteborg.

Statistical analysis
Analyses were performed using SPSS version 12.0.1. Descriptive statistics are presented as median and range or mean ± S.D. Comparisons between observed and expected BMD values were performed by sign test. Unpaired t-test was used to compare numeric data and {chi}2-test to compare categorical data. Simple regression analyses were calculated with BMD or cumulative glucocorticosteroid dose as dependent variables and demographic and disease-related variables as independent variables. Significant variables were then entered in the multiple linear regression analyses as independent variables. A forward stepwise method was used. All tests were two tailed and P < 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Ethical aspects
 Results
Discussion
 Acknowledgements
 References
 
Demographic and disease-related variables
One hundred and sixty-three female patients with SLE completed the study. Table 1 shows demographic and disease-related characteristics of the patients at examination. The median age of the participants was 47 (20–82) yrs and those who chose not to participate were in median 44 yrs old (20–90). There was no statistically significant difference in age between these two groups. Eighty-nine patients (55%) were post-menopausal and the median age at menopause was 47 (30–55) yrs. Eighty-five (52%) patients were receiving corticosteroid medication at a median dose 5 (2.5–35) mg/day. One hundred and thirty-nine (85%) patients had at some time point been on medication with glucocorticosteroids after diagnosis of SLE. Calcium and vitamin D supplementation was used by 87 patients (53%). Six patients had clinical vertebral fractures and 25 patients had peripheral osteoporotic fractures.


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  		TABLE 1. Demographic and disease-related variables in 163 female patients with SLE

 
Results from BMD measurements
Table 2 shows the results of the DXA measurements and the proportion of patients who had osteoporosis, osteopenia and normal BMD at different skeletal sites. Of these women 23, 11 and 4% had osteoporosis in at least one, two and three or more sites, respectively. The corresponding percentages for osteopenia were 56, 34 and 19% respectively. Ninety-nine patients (61%) had low BMD in at least one measured location, defined as a T-score below –1 S.D. In Table 3 and 4 the patient cohort is divided according to menopausal status. There was a significant difference in BMD between the pre- and post-menopausal groups. A low BMD measured as a T-score < –1 S.D. in at least one measured location was found in 70 of the 89 post-menopausal patients (79%) and 29 of 74 pre-menopausal women (39%). The correlation coefficient (r) between BMD in femoral neck and total hip was high r = 0.93. Regarding the other measurement sites r were lower, ranging between 0.54 and 0.69.


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  		TABLE 2. Bone mineral density and the proportion of patients with osteoporosis and osteopenia in measured sites

 

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  		TABLE 3. Bone mineral density and the proportion of post-menopausal female patients with osteoporosis and osteopenia in measured sites

 

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  		TABLE 4. Bone mineral density and the proportion of pre-menopausal female patients with osteoporosis and osteopenia in measured sites

 
BMD in SLE women compared to controls
The results revealed that in lumbar spine, hip and radius the SLE patients had significantly lower BMD than the calculated expected value. Thus, in L2-L4, 97 patients of 163 had BMD values below the expected (P < 0.05), 99 patients of 163 had values below expected BMD in total hip (P < 0.01) and 96 of 163 had lower than expected in femural neck (P < 0.01). In the diaphysal part of radius, 160 patients of 162 had BMD values below the expected BMD (P < 0.001) and 158 of 162 patients had values below the expected in the ultra distal part of radius (P < 0.001).

Markers of low BMD
Table 5 shows the demographic and disease related variables that significantly correlates to BMD. All variables significantly correlated with BMD in the simple regression were entered in the multiple regression models with the exception of variables of osteoporosis treatment, bisphosphonates and calcium plus vitamin D. In the multiple regression analyses (Table 6), known risk factors of osteoporosis, such as high age and low weight, were the most important variables associated with low BMD. Elevated markers of inflammation were significantly associated with low BMD in all measured sites except in lumbar spine. There were also significant associations between BMD and organ damage, measured with SLICC/ACR or S-creatinine. In femoral neck the variable ‘exercise’, meaning times per week with regular physical exercise, was positively associated to high BMD and in total hip ‘combinations of DMARD’ was correlated to low BMD. Neither current nor cumulative dose of glucocorticosteroids were associated with BMD in the multiple regression models.


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  		TABLE 5. Correlation coefficients (r ) obtained by regression analyses of BMD (dependent variable) and demographic and disease related factors (independent variables). Only statistically significant variables are shown

 

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  		TABLE 6. Multiple stepwise regression analysis of BMD at different sites of measurement (dependent variables) and demographic and disease-related variables (independent variables). The regression equation of BMD total hip = 1.0 – 0.005 x age (yrs) + 0.01 x BMI (kg/m2 – 0.016 x SLICC) – 0.001 x ESR (mm/h) – 0.078 x combinations of DMARD (1 = yes, 0 = no).

 
Anti-osteoporotic treatment
Sixty-five patients (76%) of those taking glucocorticosteroids (n = 85) were also taking calcium and vitamin D. Fifty-nine patients (69%) with current use of glucocorticosteroids also had a T-score < –1 S.D. in at least one measured location. Out of these patients 48 (81%) were treated with calcium and vitamin D and 21 (36%) with bisphosphonates. There were no patients with osteoporosis or osteopenia taking glucocorticosteroids and at the same time medicating with selective oestrogen receptor modulator (SERM) or HRT. Among patients with osteoporosis in at least one measured location (n = 37), irrespectively of glucocorticosteroid treatment, calcium and vitamin D was taken by 24 (65%) and bisphosphonates were taken by 13 (35%). SERM and HRT were used by one person each (3%).


   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Ethical aspects
 Results
 Discussion
Acknowledgements
 References
 
Ostoporosis and osteopenia is a significant problem for many women suffering from SLE. When interpreting the present data it is important to keep in mind that the studied SLE patients form a heterogeneous group regarding several known and possible risk factors for low BMD, such as age, weight, menopausal status, disease severity and extent of immunomodulating therapy and corticosteroid treatment. There was no statistical significant difference in age between patients included in the trial and those women who did not attend this study, but generalizations of the results to other SLE populations should be made with caution.

More than half of the studied SLE patients had lower BMD than expected and 23% were osteoporotic in at least one of the measured locations. The prevalence of osteoporosis and the BMD values are consistent with some previous reports. Gilboe and co-workers have shown very similar BMD values in a Norwegian SLE population differing only slightly from our patient population [11]. Similar findings have also been reported from SLE populations in Australia and the UK [10, 17].

Our data do show significantly lower BMD in all measured locations in post-menopausal women compared with pre-menopausal. Few pre-menopausal patients are osteoporotic but the frequency of osteopenia is 15–20% in measured locations and highest in lumbar spine and femoral neck. We do, however, not know how much the BMD reduction in post-menopausal women is dependent on lack of oestrogen or the increasing age per se.

Other age-dependent factors like accumulated corticosteroid doses and SLE disease damage scores could also influence the BMD results. Regarding pre-menopausal SLE patients, several studies have shown significantly reduced BMD [18–23]. Without the possibility of a direct comparison we looked at the BMD results from a study of postmenopausal RA patients from the same Swedish area and with exactly the same mean age as our studied postmenopausal SLE patients. The RA patients were osteoporotic to a higher degree in all measured locations than the post-menopausal SLE patients [24].

Our Swedish SLE population had BMD significantly lower than expected when compared with control BMD. The finding that 158 of 162 patients have lower BMD than expected in radius was unexpected and difficult to explain. Possibly the equation used to calculate the expected BMD value may be too insensitive for calculating a correct value regarding radius.

In simple regression analysis, known osteoporosis risk factors as well as markers of increased inflammation and disease severity were associated with low BMD. The only SLE-modifying medication associated with high BMD in our study was antimalaria treatment. If this indicates anti-inflammatory and osteoprotective properties or if antimalarias are prone to be used in mild or low inflammatory SLE with small or no need of steroid medication is not possible to say.

Lakshminarayanan and co-workers [21] have also shown an association between BMD and the use of antimalarias, but in our study the correlation did not remain in multiple regression analysis. In total hip, medication with cyclophosphamide or combinations of at least two DMARDs was associated with low BMD in simple regression but only ‘combinations of DMARD’ remained significant in multiple regression. These variables may be assumed as indicators of more severe disease.

Use of corticosteroids and bisphosphonates were associated with low BMD. If treatment with corticosteroids or the inflammatory disease itself induce low BMD in our patients is not clear. SLE disease activity often results in high ESR while CRP remains low. Since the correlation between ESR and CRP was low in our study (r = 0.21) both variables were entered in the multiple regression models.

The results from multiple regression analysis indicate that inflammation and disease damage are more important risk factors of low BMD than the glucocorticosteroid treatment itself, but even more important are known risk factors of osteoporosis like high age and low weight. Several studies have shown an association between low BMD and corticosteroids [21, 25] whereas others have failed to demonstrate such associations [9, 18, 26, 27].

Glucocorticosteroids are still one of the major medical treatments of SLE flares in spite of known adverse effects. Fifty-two per cent of the patients in our study were currently treated with cortocosteroids and 85% had at some time point been on glucocorticosteroid medication. Sixty-nine per cent of the patients with a current glucocorticosteroid use had a T-score < –1 S.D. and therefore fulfilled the criteria for anti-osteoporotic treatment according to the ACR updated recommendations and the recommendations from the Swedish Council on Technology Assessment in Health Care [28, 29]. In spite of this only one-third of these patients had medication with bisphosphonates.

Reduced BMD following glucocorticosteroid treatment has been shown in many studies to-date; regarding SLE patients the results have been conflicting. Jardinet and co-workers [30] have shown that prednisolone mean daily doses >7.5 mg contributed to bone loss after 2 yrs (P = 0.027) and Kipen and co-workers [17] showed the same for prednisolone doses ≥7.5 mg taken during 3 yrs (P = 0.02). Yee and co-workers [10] found that ever taking prednisolone >10 mg/day increased the risk for low BMD significantly. However, some studies have shown either a weak correlation between cumulated steroid treatment and BMD [27] or no correlation at all [8, 9]. Since the trabecular bone loss is more pronounced than the cortical one by glucocorticosteroid treatment, it is possible that DXA is too insensitive. Another technique of measuring BMD like quantitative computed tomography (QCT), which can distinguish between cortical and trabecular bone, would probably be more appropriate when examining patients with corticosteroid treatment and systemic inflammatory diseases.

One can also hypothesize that a low dose of corticosteroids may protect from osteoporosis by diminishing systemic inflammation, known to accelerate bone loss. On the other hand higher doses may decrease BMD by different mechanisms such as reducing bone formation by negative effects on the osteoblasts [31]. The threshold for safe use of corticosteroids regarding bone loss is therefore individual and dependent on degree of inflammation and disease duration.

Our data demonstrate that SLE patients have an increased risk of reduced BMD and osteoporosis compared with a healthy population. Substitution with calcium and Vitamin D was often given but few patients in our study were treated with anti-resorptive therapy. It is known from other studies that SLE patients with osteoporosis or fragility fractures to a low extent are treated with antiresorptive treatment [10, 20, 26]. It is not yet fully understood to which extent SLE inflammation and disease damage by itself can give rise to osteoporosis and if there are safe corticosteroid doses when used by patients with systemic inflammation. In the mean time, the finding in our study that SLE patients were at increased risk of osteoporosis compared with controls, warrant better awareness of osteoporosis and adequate treatment, to avoid fractures leading to pain, reduced quality of life or in worst cases shortening of life.


   Acknowledgements
Top
 Abstract
 Introduction
 Materials and methods
 Ethical aspects
 Results
 Discussion
 Acknowledgements
References
 
We are grateful to all of the patients in the study. We thank Anders Odén for statistical advice and support and Jesper Marmstad, GE Healthcare Sweden, for providing us with the equations for Z-score estimations. We thank Anna Jacobsson, Gunilla Håwi and Ingela Carlberg for their assistance with the patients. This study was supported by grants from the regional research sources from Västra Götaland, the Medical Society of Göteborg, Rune and Ulla Amlövs foundation for Rheumatology Research and the Swedish and Göteborg Association Against Rheumatism.

The authors have declared no conflicts of interest.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Ethical aspects
 Results
 Discussion
 Acknowledgements
 References
 

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Submitted 21 September 2006; revised version accepted 22 March 2007.
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