Longitudinal analysis of bone mineral density in pre-menopausal female systemic lupus erythematosus patients: deleterious role of glucocorticoid therapy at the lumbar spine

D. Jardinet, C. Lefèbvre1, G. Depresseux, M. Lambert1, J.-P. Devogelaer and F. A. Houssiau

Rheumatology and
1 General Internal Medicine Departments, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Bruxelles, Belgium


    Abstract
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objective. To evaluate whether bone loss occurs over time in pre-menopausal systemic lupus erythematosus (SLE) patients.

Methods. We performed a longitudinal bone mineral density (BMD) analysis in a group of 35 pre-menopausal female SLE patients. Lumbar spine and hip (total and sub-regions) BMDs were measured twice 21 ± 11 (mean ± S.D.) months apart by dual-energy X-ray absorptiometry.

Results. In the whole cohort of SLE patients, significant bone loss was observed at the lumbar spine (-1.22%/yr) but not at the total hip. Further analyses indicated that lumbar spine bone loss (-2.12%/yr) occurred exclusively in the subgroup of patients who had taken a mean prednisolone daily dose >7.5 mg between the two BMD measurements. Moreover, bone loss was more important in patients who had previously received a cumulative prednisolone dose <=5 g by the time of their first BMD evaluation.

Conclusions. These results, by demonstrating a loss of lumbar spine bone over time in pre-menopausal SLE patients given glucocorticoid (GC) therapy, strongly support the use of preventive treatment to minimize GC-induced osteoporosis in pre-menopausal female SLE patients given prednisolone daily doses >7.5 mg.

KEY WORDS: SLE, Osteoporosis, Glucocorticoids, BMD, Longitudinal, Pre-menopausal females.


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Several cross-sectional studies have indicated that pre-menopausal female patients with systemic lupus erythematosus (SLE) suffer from significant trabecular and cortical bone loss [1–8], with, however, conflicting results regarding the causal role of glucocorticoids (GC) in this process. We [5] and others [3, 7] found that the degree of bone loss in SLE patients was commensurate with their cumulated oral GC intake, a correlation that was not confirmed in other studies [1, 2, 4, 6, 8]. Moreover, and somewhat surprisingly in view of the cross-sectional data, the very few longitudinal studies performed in small groups of pre-menopausal SLE patients failed to prove a significant bone loss over time [3, 6, 9], a discrepancy that might be related to the kinetics of GC-induced bone loss, which is maximal in the first year of therapy [10].

We performed a longitudinal bone mineral density (BMD) analysis in a group of 35 pre-menopausal female lupus patients in order to evaluate whether lumbar spine and/or hip bone loss occurred over time, in particular in patients given a mean prednisolone daily dose >7.5 mg and in those studied early after initiation of GC therapy.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
We measured BMDs twice in 35 pre-menopausal (defined as menstruating regularly) female patients fulfilling the American Rheumatism Association (ARA) classification criteria for SLE [11]. As repeated BMD measurements are part of standard clinical practice in GC-treated patients, we considered our analysis as an audit of experience with an accepted management plan. Therefore, formal approval from a research ethics committee was not sought. The mean (±S.D.) age was 30 (±9) yr and mean (±S.D.) disease duration was 11 (±7) yr. Patients with impaired renal function (serum creatinine >=1.3 mg/dl) and heavy smokers (>20 cigarettes/day) were excluded from this study.

At baseline, 29 of the 35 SLE patients had ever received GC, with a mean (± S.D.) cumulated equivalent prednisolone intake of 15.8 (± 14.9) g (calculated for the 28 patients for whom precise treatment data were available). Between the two BMD analyses, seven patients did not receive GC, while 28 others were treated with a mean (± S.D.) prednisolone daily dose of 9.3 (± 5.3) mg. None of the patients was given calcium or vitamin D supplements.

Lumbar spine (L1–L4) and hip (total hip, neck, trochanter, intertrochanter and Ward's triangle) BMDs were measured by dual-energy X-ray absorptiometry (DXA) with a Hologic QDR 1000 W densitometer (Hologic Inc., Waltham, MA, USA). The reproducibility of the technique, i.e. the coefficient of variation, was 0.8% at the spine and 1.6% at the total hip [12]. BMD values (g/cm2) were also expressed in Z-scores, i.e. the difference in S.D. compared with healthy age- and sex-matched controls. Hologic pre-menopausal controls were used because they had been validated in our centre for young healthy Belgian females.

Fasting serum titres of total alkaline phosphatase (normal range: 10–60 IU/l) and C-terminal telopeptides of type I collagen [CTX; Serum CrossLapsTM ELISA, Osteopark, Herlev, Denmark; mean S.D.) values in normal pre-menopausal women: 1748 (± 740) pM, according to the manufacturer] were measured at baseline in 18 patients. Urinary concentrations of calcium, creatinine, hydroxyproline and amino-terminal telopeptides of type I collagen (NTX; OsteomarkR ELISA, Ortho-Clinical Diagnostics, Rochester, USA) were measured at baseline in the second fasting urine spot in 13 patients. The mean (± S.D.) fasting urinary NTX/creatinine ratio measured in normal pre-menopausal women is 35 (± 15) nM/mM, according to the manufacturer.

Statistical analyses were performed using Student's t-test for paired or unpaired values. Simple linear regression analysis was used to correlate BMD values and oral GC intake.


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Baseline BMD measurements confirmed the presence of significantly reduced BMDs in pre-menopausal SLE patients compared with healthy age-matched female controls, with a mean [ ± standard error of the mean (S.E.M.)] Z-score of -0.66 (± 0.2) at the lumbar spine (P < 0.005 vs controls) and of -0.89 (± 0.18) at the total hip (P < 0.0001 vs controls). As anticipated from our previous cross-sectional study [5], baseline BMD values were negatively correlated with the cumulated oral GC intake by the time of the first BMD evaluation [r = -0.47 at the lumbar spine (P < 0.005) and r = -0.47 at the hip (P < 0.005)].

Repeated BMD measurements, performed after a mean (±S.D.) follow-up period of 21 (±11) months, indicated a significant bone loss at the lumbar spine (-1.22%/yr; P = 0.01 vs no change) but not at the hip (total hip, neck and trochanter) (Table 1Go). Interestingly, when patients were divided according to their mean prednisolone daily dose taken in the time interval between the two BMD measurements, a positive correlation was found between bone loss and GC intake over time. Thus, as illustrated in Fig. 1Go, significant (P = 0.027) lumbar bone loss (- 2.12%/yr) was observed only in the group of patients (n = 15) who had taken a mean prednisolone daily dose >7.5 mg between the two BMD analyses, while no bone loss occurred over time in untreated patients (n = 7) nor in those given a mean prednisolone daily dose <=7.5 mg.


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TABLE 1. Longitudinal BMD changes in SLE patients

 


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FIG. 1. Lumbar BMD changes over time according to the mean individual prednisolone daily dose during the study period. BMD changes are expressed as mean (± S.E.M.) % per year of follow-up. Patients categorized in the ‘0–7.5’ group had received a mean (± S.D.) prednisolone daily dose of 5.1 (± 1.6) mg (range: 1.6–7.5) during follow-up, while patients categorized in the ‘>7.5’ group had received a mean (± S.D.) prednisolone daily dose of 12.9 (± 4.5) mg (range: 7.7–21.0) during follow-up. No statistical differences were noted between the three groups regarding age, body mass index (BMI) and baseline BMD (data not shown). P = 0.027 by unpaired t-test vs no change.

 
Since GC-induced bone loss is purported to be maximal during the first year(s) of therapy, we hypothesized that bone loss during the longitudinal study was negatively correlated to the cumulated amount of GC received by the time of the first BMD measurement. Accordingly, as indicated in Fig. 2Go, a significant (P = 0.004) lumbar bone loss occurred over time exclusively in patients who had previously received a cumulative prednisolone dose <=5 g by the time of the first BMD evaluation and not in those who had taken higher cumulated doses (>5 g).



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FIG. 2. Lumbar BMD changes over time according to the individual cumulated GC intake at baseline. BMD changes are expressed as mean (± S.E.M.) % per year of follow-up. Only the 28 patients given GC therapy within the follow-up period were considered for this analysis. Patients categorized in the ‘>5’ group had received a mean (± S.D.) cumulated prednisolone dose of 21.6 (± 15) g (range: 5.4–56) at baseline, while patients categorized in the ‘<=5’ group had received a mean (± S.D.) cumulated prednisolone dose of 1.7 (± 1.7) g (range: 0–4.1) at baseline. Patients categorized in the ‘<=5’ group were younger (26 ± 6 yr vs 36 ± 10; P < 0.01 by unpaired t-test). No statistical differences were noted between the two groups regarding body mass index (BMI). As anticipated, baseline lumbar spine BMD was lower in the patients given a cumulated individual prednisolone dose at baseline >5 g (1.02 ± 0.08 vs 0.88 ± 0.11 g/cm2; P < 0.005 by unpaired t-test). *P = 0.004 by unpaired t-test vs no change.

 
We evaluated whether baseline titres of biochemical markers of bone turnover predicted bone loss over time. At baseline, the mean (± S.D.) serum total alkaline phosphatase level (36 ± 28 IU/l) and fasting urinary calcium/creatinine ratio (0.09 ± 0.16 mg/mg) were within the normal range, whereas the mean (± S.D.) serum CTX concentration (3128 ± 1710 pM), urinary hydroxyproline/creatinine ratio (35 ± 22 µg/mg) and urinary NTX/creatinine ratio (90 ± 39 nM/mM) were elevated, compared with values measured in normal pre-menopausal women. No correlation could be found between BMD changes over time and baseline titres of any biochemical marker of bone turnover.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The results of this longitudinal BMD analysis performed in pre-menopausal SLE patients, thus far the largest available, demonstrate that lumbar spine bone loss occurs over time in a subset of SLE patients receiving a mean prednisolone daily dose >7.5 mg. This conclusion might appear trivial given the well-known deleterious role of GC on bone mass in many other rheumatic diseases [13–15], the mechanisms of which include inhibition of intestinal calcium absorption (causing secondary hyperparathyroidism), inhibition of bone formation, enhanced bone resorption and decreased gonadal steroid production [16].

It should be stressed, however, that the few published longitudinal BMD studies performed in small groups of pre-menopausal SLE patients surprisingly failed to prove a significant bone loss over time in GC-treated patients [3, 6, 9]. Thus, Pons et al. [3] did not find significant BMD changes over a 3-yr follow-up period in a group of 21 pre-menopausal SLE patients given a mean prednisolone daily dose of 7.9 mg, even in the subset of patients given a mean dose >=7.5 mg/day. Similarly, the study by Formiga et al. [9] did not indicate bone loss in a group of 25 pre-menopausal GC-treated SLE patients given a mean prednisolone daily dose of 9.2 mg and followed-up for a period of 18 months. Finally, Hansen et al. [6] came to similar conclusions in a group of 20 pre-menopausal SLE patients, although no precise data are available regarding GC therapy.

The results of these three longitudinal studies contrast with those of the cross-sectional analyses performed in SLE patients, which all—but one—have demonstrated significantly reduced BMDs [1–8]. The kinetics of GC-induced bone loss, which is maximal in the first year(s) of treatment, might explain this discrepancy. Thus, by the time of baseline BMD evaluation, the patients investigated by Formiga et al. [9] and by Pons et al. [3] had already received a cumulated prednisolone dose of 35 and 25 g, respectively. By contrast, our GC-treated SLE patients had only received half this amount of prednisolone at baseline BMD, which might explain that they were more susceptible to further GC-induced bone loss. Accordingly, when our patients were divided into two groups based on the amount of GC they had received by the time of their first BMD study (>5 g or <=5 g of prednisolone), only those who had taken <=5 g significantly lost bone during follow-up.

The reasons why hip BMDs did not change over time in GC-treated pre-menopausal SLE patients, even in those receiving a mean prednisolone daily dose >7.5 mg, are speculative. A tempting explanation could be related to the fact that trabecular bone is more sensitive to GC than cortical bone [16], which might explain why bone loss occurred over time at the lumbar spine (a predominantly trabecular site) but not at the hip (a mixed trabecular/cortical site). It should be stressed, however, that we did not find a significant bone loss at the hip sub-regions which contain a significant amount of trabecular bone, except at Ward's triangle, for which the reproducibility of the DXA technique is poorer than for the total hip.

The negative impact of GC therapy on lumbar spine BMD of SLE patients contrasts with the rather neutral effect of GC on BMDs of pre-menopausal rheumatoid arthritis patients given a fixed dose of 7.5 mg prednisolone/day [17]. In this respect, it should be stressed that SLE patients, very much in contrast to rheumatoid arthritis patients, receive peak GC doses rather than fixed doses, the former potentially interfering more with bone metabolism owing to a higher parathyroid reaction.

Taken together, the results of this longitudinal analysis strongly suggest that pre-menopausal SLE patients treated with prednisolone doses >7.5 mg/day have an increased risk of future vertebral crushes. This conclusion implies that preventive treatment should be applied to pre-menopausal SLE patients given GC to minimize GC-induced osteoporosis. In this respect, several recent studies have demonstrated that effective prevention can be achieved with bisphosphonates through their potent anti-resorbing properties. Some of these compounds were found to prevent GC-induced BMD loss [18] and—more importantly—to reduce the incidence of fractures, in particular of vertebral crushes [19].


    Notes
 
Correspondence to: F. A. Houssiau. Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

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Submitted 13 May 1999; revised version accepted 21 October 1999.