Factors affecting bone mineral density in children and adolescents with systemic lupus erythematosus

Su Jin Park; Soo Yeun Sim; Dae Chul Jeong; Byung-Kyu Suh; Moon Bae Ahn

doi:10.6065/apem.2346060.030

Ann Pediatr Endocrinol Metab > Volume 29(3); 2024 > Article

Park, Sim, Jeong, Suh, and Ahn: Factors affecting bone mineral density in children and adolescents with systemic lupus erythematosus

Original Article

Annals of Pediatric Endocrinology & Metabolism 2024;29(3): 191-200.

Published online: January 28, 2024

DOI: https://doi.org/10.6065/apem.2346060.030

Factors affecting bone mineral density in children and adolescents with systemic lupus erythematosus

Department of Pediatrics, College of Medicine, The Catholic University of Korea, Seoul, Korea

Address for correspondence: Moon Bae Ahn Department of Pediatrics, College of Medicine, The Catholic University of Korea, 222 Banpodaero, Seocho-gu, Seoul, 06591, Korea Email: mbahn@catholic.ac.kr

Received March 2, 2023 Revised May 1, 2023 Accepted July 7, 2023

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Purpose

Patients with juvenile-onset systemic lupus erythematosus (JSLE) are at a high risk of entering adulthood with disease-related morbidities like reduced bone mass and osteoporosis. This study aimed to evaluate the clinical characteristics of JSLE and to analyze the factors associated with low bone mineral density (BMD) in these patients.

Methods

Children and adolescents diagnosed with JSLE at a single institution in Korea were included. Demographic, clinical, and laboratory data as well as details about the use of glucocorticoids (GCs) and disease-modifying antirheumatic drugs were collected. The lumbar spine (LS) BMD z-score was measured using dual energy x-ray absorptiometry, and lateral thoracolumbar spine radiographs were collected.

Results

A total of 29 patients with JSLE were included in this study. Of these patients, 7 had a BMD z-score of -2.0 or lower and were designated as the low BMD group. The differences in the clinical parameters and treatment variables between the low BMD and non-low BMD groups were compared. Higher cumulative GC dose, longer GC exposure, and higher cumulative hydroxychloroquine (HCQ) dose were all associated with low BMD; among them, the main factor was the duration of GC exposure. There was no significant correlation between BMD and clinical profile, disease activity, or bone-metabolism markers.

Conclusions

The duration of GC exposure, cumulative GC dose, and cumulative HCQ dose were risk factors for low BMD in patients with JSLE, with the main factor being the duration of GC exposure. Thus, patients with JSLE should be routinely monitored for low BMD and potential fracture risks, and GC-sparing treatment regimens should be considered.

Keywords: Bone density, Metabolic bone diseases, Glucocorticoids, Juvenile osteoporosis, Systemic lupus erythematosus

Highlights

· Patients with juvenile-onset systemic lupus erythematosus are at a high risk of entering adulthood with disease-related morbidities like reduced bone mass and osteoporosis.

· Longer duration of glucocorticoid (GC) exposure, higher cumulative GC dose, and higher cumulative hydroxychloroquine dose were associated with low bone mineral density (BMD) in patients with juvenile-onset systemic lupus erythematosus (JSLE), with the main risk factor being the duration of GC exposure.

· Patients with JSLE should be routinely monitored for low BMD and potential fracture risks, and GC-sparing treatment regimens should be considered.

Introduction

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disorder characterized by chronic inflammation and damage to various organs, including the skin, joints, blood cells, brain, and kidneys [1]. Juvenile-onset SLE (JSLE) represents 15%–20% of all SLE cases, and the course of JSLE is often more severe than that of adult SLE, with a greater frequency of aggressive renal disease and a higher requirement for steroids and immunosuppressive drugs [2]. In recent studies, the overall prognosis for SLE has improved to a 10-year survival rate of >90% [3]. However, their longer survival means that patients with SLE now experience more complications and that patients with JSLE are at a greater risk of entering adulthood with disease-related morbidities like reduced bone mass and osteoporosis [4]. Furthermore, patients with JSLE are at considerable risk for developing low bone mass since they are affected by the disease before achieving peak bone mass, which serves as a future bone bank.

Several factors may adversely affect bone health in patients with JSLE, including systemic inflammation, hormonal factors, decreased physical activity, limited sunlight exposure, and inadequate calcium and vitamin D intake [5,6]. Treatments, primarily glucocorticoids (GCs) and possibly some diseasemodifying antirheumatic drugs (DMARDs), may also have a negative impact on bone health [7]. GCs are well known to reduce bone formation and increase bone resorption. However, they may also have favorable effects on bone mass through the reduction of systemic inflammation [8]. Several cross-sectional studies have assessed the effects of GC use on bone mass in adult patients with SLE, and, although some controversies remain, GCs were reported to be a risk factor for low bone mass and fractures.9-1

However, few studies to date have investigated bone health in patients with JSLE. A few cross-sectional studies on bone health in children with rheumatic disorders have reported low bone mass and an increased prevalence of fractures in this population [14-17]. Trapani et al. [14] documented a significant inverse correlation between bone mineral density (BMD) and cumulative GC dose in patients with JSLE, while Valta et al. found no correlation between BMD and cumulative GC dose in patients with juvenile idiopathic arthritis [17]. A prospective study from the Canadian Steroid-associated Osteoporosis in the Pediatric Population consortium reported that every 0.5-mg/kg increase in the average daily GC dose was associated with a 2-fold increased risk of fracture among children with rheumatic disorders, including juvenile dermatomyositis, juvenile idiopathic arthritis, systemic vasculitis, and JSLE [18].

This study aimed to evaluate the clinical characteristics of patients with JSLE and to analyze the factors associated with low BMD in these patients.

Materials and methods

1. Subjects

Children and adolescents diagnosed with JSLE from January 1, 2009, to April 30, 2022, at a single institution in Korea were included. The diagnosis was made by pediatric rheumatologists using the American College of Rheumatology and Systemic Lupus International Collaborating Clinics' classification criteria [19-21]. In this study, patients with JSLE were defined according to the definition of Silva et al. [22], which consists of SLE onset before 18 years of age, a threshold based on different gender distribution, clinical course and disease activity from adult SLE. Only patients who had undergone dual energy x-ray absorptiometry (DXA) and thoracolumbar spine radiography were considered eligible for enrollment. Patients who had received GC treatment for <3 months were excluded. This study was approved by the Institutional Review Board (IRB) of Seoul St. Mary's Hospital (IRB No. KC22RISI0496). The need for written informed consent was waived due to the retrospective nature of the study.

2. Clinical and laboratory data of JSLE

Demographic, clinical, and laboratory data, including age, height, weight, body mass index, pubertal stage, course of disease, bone-metabolism markers, serologic markers of SLE activity, and use of GCs and DMARDs, were collected. All data were collected from each patient at 2 time points: diagnosis and follow-up (the time when the latest DXA was performed).

The clinical manifestations and disease course were evaluated. Organ involvement was assessed in 5 categories: skin, joint, hematologic, and renal involvement and neuropsychiatric SLE. Skin involvement was categorized based on the presence of malar rash or photosensitivity. Joint involvement was defined as the presence of swelling or effusion in 2 or more joints. Hematologic involvement was defined by the presence of one of the following: hemolytic anemia (hemoglobin<10.0 g/dL with evidence of hemolysis), leukopenia (white blood cell count<4.0 × 109/L), and thrombocytopenia (platelet count<100 x 109/L). Renal involvement was defined as histological renal damage or the presence of proteinuria (>0.5 g within 24 hours). Neuropsychiatric SLE was designated according to the American College of Rheumatology nomenclature [23]. Disease activity was assessed using the revised version of the SLE Disease Activity Index (SLEDAI) [24]. A SLE flare was defined as new or worsening clinical symptoms with escalation of treatment (i.e., new immunosuppressant use, a prednisone increase of 0.5 mg/kg/day, intravenous methylprednisolone, or hospitalization). Serological markers related to SLE disease activity were collected. Low C3 and C4 complement levels and high titers of anti-dsDNA antibodies were considered reflective of greater SLE activity [25].

The cumulative GC dose (expressed as the prednisoloneequivalent dose) was calculated according to each patient’s mean body weight (from diagnosis to follow-up) and presented in grams per kilogram. The average daily dose is presented as grams per kilogram per day. The duration of exposure was assessed, excluding periods when GC was discontinued due to improvement or remission of the disease. The use of hydroxychloroquine (HCQ) and other DMARDs (azathioprine, methotrexate, mycophenolate mofetil, and cyclosporine) was recorded from diagnosis to follow-up.

3. Bone assessment

The lumbar spine (LS) BMD (L1–4) was measured in all patients using DXA (Horizon W DXA system, Hologic Inc., Marlborough, MA, USA). All DXA data recorded from diagnosis to most recent follow-up were collected. The BMD z-score was calculated and compared with those of 1,650 healthy age- and sex-matched Korean controls [26]. Lateral thoracolumbar spine radiographs were collected from diagnosis to follow-up, when the latest DXA was performed. Spine radiographs were scored independently by 2 pediatric radiologists according to the modified Genant semiquantitative method [27]. Vertebral bodies were graded according to the extent of reduction in height ratios: 20%–25% (mild), 25%–40% (moderate), and >40% (severe). Bone-metabolism markers of interest included calcium, phosphorous, alkaline phosphatase, 25-hydroxyvitamin D, and parathyroid hormone, which were assessed at both diagnosis and follow-up.

4. Statistical analysis

Results are reported as median (interquartile range [IQR]) values for continuous variables and as proportions for categorical variables. Anthropometric data, clinical features, disease-related serological markers, bone-metabolism markers, cumulative dose and duration of GCs, and cumulative HCQ dose were compared with respect to a LS BMD of -2.0 using the nonparametric Mann-Whitney U-test. The proportion of DMARD use was compared with respect to a -2.0 LS BMD using the chi-square test. Linear regression analysis and univariate binominal logistic regression were performed to identify risk factors for low BMD. Variables identified as significant in the univariate analysis were entered into a multiple logistic regression model. Statistical calculations were performed using IBM SPSS Statistics ver. 27.0 (IBM Co., Armonk, NY, USA). Two-tailed P values of <0.05 were considered statistically significant.

Results

1. Demographic and clinical characteristics

A total of 29 patients with JSLE (25 women and 4 men) were included in this study. SLE was diagnosed at a median age of 12.7 (interquartile range [IQR], 11.5–14.8) years, and the median age at follow-up was 15.8 (IQR, 13.6–17.5) years. All patients were treated with GCs at a median daily dose of 9.9 mg, with a median cumulative dose of 14.6 g, during their median follow-up period of 4.5 (IQR, 2.2–6.9) years. The median (IQR, 25%–75%) LS BMD z-score at follow-up was -0.9 (-1.8 to 0.1) points. The prevalence of vertebral fractures (VFs) at followup was 52%, with mild, moderate, and severe fractures totaling 24%, 21%, and 10% of these, respectively. Since the presence of at least one vertebral compression fracture in the absence of local disease or high-energy trauma meets the definition for osteoporosis in children and adolescents, the prevalence of osteoporosis in the present study was 52%. The demographic data, clinical characteristics, and laboratory characteristics of the subjects at both diagnosis and the time of the latest DXA are summarized in Table 1.

2. Comparison of clinical parameters with respect to a LS BMD z -score of -2.0

Based on the latest DXA, patients with a LS BMD z-score of ≤-2.0 were classified as the low BMD group, while others were classified as the non-low BMD group. Of the 29 patients, 7 had a LS BMD z-score of ≤-2.0 points and were designated as the low BMD group. The differences in the clinical parameters between the low BMD and non-low BMD groups are summarized in Table 2 and Supplementary Table 1.

The comparison of anthropometric data at diagnosis and follow-up revealed that the low BMD group had a lower height z-score at both diagnosis (-0.043 vs. -1.651, P=0.014) and follow-up (-0.504 vs. -1.843, P=0.013) compared to the nonlow BMD group. There were no significant differences in weight and body mass index. There were no differences in clinical profiles (skin, joint, hematologic, and renal involvement and neuropsychiatric SLE), SLEDAI scores, or the number of flareup episodes between the 2 groups. The serological markers reflecting SLE disease activity and bone-metabolism markers also demonstrated no difference between the 2 groups at both diagnosis and follow-up. The low BMD group had a higher prevalence of a ≤-1.0 initial LS BMD z-score (27% vs. 100%, P<0.001) compared to the non-BMD group. The prevalences of moderate VFs (9% vs. 43%, P<0.001) and severe VFs (0% vs. 43%, P<0.001) were also higher in the low BMD group than in the non-low BMD group.

3. Comparison of medication use with respect to a LS BMD z -score of -2.0

Medication use was compared with respect to a LS BMD z-score of -2.0 (Supplementary Table 2). All patients with JSLE used GCs and HCQ from the onset of their disease. The duration of GC exposure was significantly longer in the low BMD group (2.9 years vs. 6.9 years, P=0.002) than in the nonlow BMD group. The total cumulative dose (12.3 g vs. 26.8 g, P=0.021) and cumulative dose per mean body weight (0.23 g/kg vs. 0.54 g/kg, P=0.027) were also significantly higher in the low BMD group than in the non-low BMD group. However, there was no difference in the daily GC dose between the 2 groups (Fig. 1).

Tapering or discontinuation of medication was attempted with GCs but not with HCQ throughout the disease course of the present cohort. Four out of the 29 patients discontinued using GCs, although one of them restarted GC treatment due to increased disease activity. In contrast, all patients continued on HCQ from diagnosis to follow-up, and discontinuation or tapering of this medication was not attempted in any patient. This is consistent with the 2019 EULAR (European Alliance of Associations for Rheumatology) recommendations prescribing HCQ for all patients with SLE, unless contraindicated. In contrast, GC discontinuation is recommended whenever possible [28]. As the duration of HCQ was not a modifiable factor, we compared the cumulative HCQ doses between the two groups, which were 4.64 g/kg in the non-low BMD group and 10.10 g/kg in the low BMD group, respectively (P=0.003) (Fig. 1).

Other DMARDs used by cohort patients included azathioprine (55%), methotrexate (34%), mycophenolate mofetil (31%), and cyclosporine (10%). There was no significant difference in the use of DMARDs other than HCQ between the 2 groups. Regarding antiosteoporosis treatment, bisphosphonate use was significantly more common in the low BMD group (0% vs. 57%, P<0.001) than in the non-low BMD group.

4. Association between GC, HCQ, and low BMD

Considering that both the cumulative dose and duration of GC therapy and the cumulative HCQ dose were greater in the low BMD group, we further analyzed the association between GCs, HCQ, and LS BMD. Linear regression analyses demonstrated that the cumulative GC dose, duration of GC exposure, and cumulative HCQ dose had a statistically significant inverse relationship with the LS BMD z-score (Fig. 2).

The 3 treatment variables (cumulative dose and duration of GCs and cumulative HCQ dose) were entered into univariate logistic regression analyses for low BMD (LS BMD z-score ≤-2.0). The duration of GC exposure was significantly associated with low BMD (odds ratio [OR], 3.17; P=0.020). The cumulative GC dose (OR, 1.005; P=0.043) and HCQ dose (OR, 1.000; P=0.017) were also statistically significant, but with low relevance to a LS BMD z-score of ≤-2.0 compared to the duration of GC exposure. We performed a multivariate logistic regression analysis, including the 3 aforementioned variables; however, Pearson correlation test revealed that the 3 variables were highly correlated, rendering the model unstable. Both the duration of GC therapy and the cumulative HCQ dose were particularly interrelated, with a Pearson correlation coefficient of 0.92 (P<0.001). Therefore, we performed 3 separate analyses incorporating 2 of these 3 variables at a time for low BMD (Table 3). The best model for low BMD was the model including the duration of GC therapy and the cumulative GC dose, and the results of this analysis demonstrated that the duration of GC therapy best predicted low LS BMD (OR, 4.486; 95% confidence interval [CI], 1.035–19.445; P=0.045).

5. Association between other clinical variables and low BMD

Since the low BMD group had lower height z-score than the non-low BMD group, we further analyzed whether height deficit is a risk factor for low BMD. We adjusted the LS BMD z-score for body size [26] in 2 children with short stature (height z-score<-2.0) and performed a univariate logistic regression for low BMD. We found that height at diagnosis (P=0.093) and follow-up (P=0.108) were not risk factors for low BMD. As mentioned above, the low BMD group had a greater prevalence of a -1.0 or lower initial LS BMD z-score. Another logistic regression analysis was performed; ultimately, however, an initial LS BMD z-score ≤-1.0 was not a relevant risk factor for low BMD (P=0.994).

Discussion

The present study focused on low BMD in patients with JSLE and showed that longer duration of GC exposure, higher cumulative GC dose, and higher cumulative HCQ dose are associated with low BMD in patients with JSLE, with the main risk factor for low BMD being the duration of GC exposure. We found no significant correlation between LS BMD and clinical profile, SLE disease activity, or bone-metabolism markers. There was also no significant difference in the use of DMARDs, other than HCQ, between the low and non-low BMD groups.

Although a recent meta-analysis failed to show a correlation between GC use and low BMD in adult patients with SLE [9], several studies to date have demonstrated an association between GC use and low BMD [10-13)]. However, the results are inconsistent regarding whether the cumulative dose, treatment duration, or both, are risk factors for low BMD. Davidson et al. [11] reported that the cumulative steroid dose is significantly associated with osteoporosis (OR, 1.60; 95% CI, 1.07–2.41), whereas the duration of GC exposure is not. A recent metaanalysis of secondary osteoporosis in adult patients with SLE revealed that both the cumulative GC dose and the duration of GC therapy were significantly different between patients with and without osteoporosis [13]. Studies concerning the pediatric SLE population are scarce and have mostly focused on daily or cumulative doses of GCs rather than the duration of GC exposure. Nakhla et al. [15] reported that significant risk factors for VFs in patients with JSLE include cumulative GC dose, but the duration of GC exposure was not analyzed. A reduction in LS BMD was significantly associated with higher cumulative GC doses in the study by Lilleby et al. [4], but the authors assessed the duration of GC exposure as "current GC use or not" and did not include a specific duration. Furthermore, an increase in the average daily GC dose was shown to be associated with an increase in VF risk (hazard ratio, 1.95; 95% CI, 1.08–3.51), whereas GC intensity and the duration of GC therapy were not [29]. Our study investigated both the effect of cumulative GC dose and the effect of the duration of GC exposure on BMD and revealed that the duration of GC exposure is a notable risk factor for low BMD in patients with JSLE. This result is clinically meaningful because it may support the applicability of more aggressive use of intravenous methylprednisolone pulses upon diagnosis, which might allow for faster tapering and discontinuation of oral GCs, shortening the duration of GC exposure. Another approach may include the early initiation of immunosuppressants to facilitate tapering and discontinuation of GCs. These 2 approaches may minimize the duration of GC exposure, which may be beneficial to bone health in patients with JSLE.

HCQ is an antimalarial agent given to all patients with SLE. HCQ treats skin disease, minimizes flare-ups, and decreases auto-antibody production by inhibiting Toll-like receptor pathways [30]. In the present study, all patients used HCQ, and the cumulative HCQ dose was greater in the low BMD group, although this was not a significant risk factor for low BMD in multivariate analyses. Data regarding the effects of HCQ on bone health are scarce, and the results are conflicting. Two crosssectional studies documented higher spinal BMD associated with HCQ use, suggesting a protective effect of HCQ on bone [31,32]. In contrast, a 6-year Dutch study reported that hip BMD loss was associated with HCQ use [10]. Meanwhile, a more recent study involving 1807 adult patients with SLE found no correlation between HCQ use and BMD [33]. The impact of immunosuppressant drugs on bone health is also controversial, and it is difficult to clearly discern their effect on bone because their use usually implies a more severe SLE disease status. Methotrexate and azathioprine are considered in patients when trials with GC and HCQ or HCQ alone are insufficient to control symptoms. However, although there have been reports of patients developing multiple insufficiency fractures while on prolonged methotrexate therapy, commonly known as methotrexate osteopathy, the effects of methotrexate on bone loss are not fully understood [34,35]. An observational study of 60 patients with rheumatic arthritis did not reveal a significant difference in BMD between methotrexate users and nonusers [36]. There are minimal data on azathioprine and BMD, but a study concerning patients with Crohn disease demonstrated that azathioprine did not affect the BMD itself; however, it seemed to have a protective effect on bone mass via steroid sparing [37]. Furthermore, a recent large cross-sectional study by Cramarossa et al. [33] showed no association between immunosuppressant use and BMD. The association between DMARD use and bone loss requires further investigation.

A recent meta-analysis of secondary osteoporosis in SLE showed that, among 9 studies that reported SLEDAI scores, there was no significant difference in SLEDAI scores between patients with or without osteoporosis and SLE [13]. This result was consistent with that of our study, which showed no correlation between SLEDAI score and low BMD. In a large 5-year study of adult female patients with SLE, Zhu et al. [38] reported that SLE flares during follow-up were significantly associated with a greater reduction in LS BMD. We also investigated the relationship between flare-ups and BMD. In our study, 71% of the low BMD group and 32% of the non-low BMD group experienced flare-ups, but this difference was not statistically significant. In short, in our study, there was no significant correlation between disease activity and low BMD. In addition to SLEDAI scores and flare-ups, there was also no significant correlation between the clinical profile, serological markers of SLE activity, bone-metabolism markers, and low BMD. Although this is a negative finding, it may imply that clinical manifestations, SLEDAI score, and serological markers cannot predict low bone mass in patients with JSLE, and routine surveillance of BMD and VFs is necessary to detect early reductions in bone mass.

In the present study, the low BMD group had a lower z-score at both diagnosis and follow-up. Several studies have reported that BMD increases with height and weight [39,40]. In other words, lower height and weight values are associated with lower BMD. Although height deficit was not proven to be a risk factor for low BMD in our study, the fact that the low BMD group had lower z-scores at diagnosis and follow-up may imply that patients with JSLE with short stature should be more cautiously monitored for a decline in BMD and growth.

This study has some limitations owing to its retrospective design. First, the total number of patients with JSLE who had undergone DXA imaging and thoracolumbar spine radiography was small. Some patients did not have sufficient DXA data or spine radiographs at diagnosis, which limited further comparison of DXA data during early stages of treatment and/or at follow-up. Further prospective studies are needed to determine the effects of GCs and DMARDs on low BMD. Second, the dietary calcium and vitamin D intake and the amounts of physical activity and sunlight exposure could not be accurately assessed by chart review. Lastly, BMD analysis by DXA did not consider three-dimensional bone microarchitecture and volumetric BMD. We did not have access to quantitative measures assessed by computed tomography. However, the strength of this study is that we performed a comprehensive analysis of the effects of anthropometric, clinical, laboratory, and treatment-related variables on BMD in patients with JSLE.

In conclusion, a longer duration of GC exposure and higher cumulative GC and HCQ doses are risk factors for low BMD in patients with JSLE, with the main risk factor among them being the duration of GC exposure. Disease-activity markers of SLE and bone-metabolism markers do not predict low BMD. Thus, patients with JSLE should be routinely monitored for low BMD and potential fracture risks, and GC-sparing treatment regimens should be considered for patients with JSLE to shorten GC exposure.

Supplementary materials

Supplementary Tables 1–2 can be found via https://doi.org/10.6065/apem.2346060.030.

Supplementary Table 1.

Comparison of clinical parameters with respect to a LS BMD z-score of -2.0

apem-2346060-030-Supplementary-Table-1,2.pdf

Supplementary Table 2.

Comparison of medication use with respect to a LS BMD z-score of -2.0

apem-2346060-030-Supplementary-Table-1,2.pdf

Notes

Conflicts of interest

No potential conflict of interest relevant to this article was reported.

Funding

This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Data availability

The data that support the findings of this study can be provided by the corresponding author upon reasonable request.

Author contribution

Conceptualization: SJP; Data curation: SJP; Formal analysis: SJP; Methodology: SJP; Visualization: SJP; Writing - original draft: SJP; Writing - review & editing: SJP, SYS, DCJ, BKS, MBA

Fig. 1.

Comparison of GCs and HCQ with respect to a LS BMD z-score of -2.0. The low BMD group had a longer duration of GC exposure, higher cumulative GC dose, and higher cumulative HCQ dose compared to the nonlow BMD group, but there was no difference in daily GC dose between the 2 groups. (A) GC duration. (B) Cumulative GC. (C) Daily GC. (D) Cumulative HCQ. GC, glucocorticoids; HCQ, hydroxychloroquine; LS lumbar spine; BMD, bone mineral density. Cumulative GC doses are expressed as prednisolone-equivalent doses.

Fig. 2.

Linear regression model of treatment variables and LS BMD z-score. The linear regression model shows an inverse relationship between LS BMD z-score and the following factors: duration of GC exposure, cumulative GC dose, and cumulative HCQ dose. (A) GC duration. (B) Cumulative GC. (C) Cumulative HCQ. GC, glucocorticoids; HCQ, hydroxychloroquine; LS BMD, lumbar spine bone mineral density.

Table 1.

Demographics and clinical and laboratory characteristics of the study subjects

Variable	Diagnosis (n=29)	Follow-up (n=29)
Age (yr)	12.7 (11.5–14.8)	15.8 (13.6–17.5)
Female sex	25 (86.2)	25 (86.2)
Tanner stage	3 (1–4)	5 (4–5)
Disease duration	-	4.5 (2.2–6.9)
Anthropometry
Height z-score	-0.4 (-0.9 to 0.7)	-0.7 (-1.3 to 0.4)
ΔHeight z-score	-	-0.1 (-0.3 to 0)
Weight z-score	-0.3 (-1.2 to 0.8)	-0.1 (-1 to 1.2)
ΔWeight z-score	-	0.2 (-0.4 to 1.0)
BMI z-score	0.1 (-1.2 to 1.0)	0 (-0.7 to 1.0)
ΔBMI z-score	-	0.3 (-0.1 to 1.1)
Clinical profile of SLE
Skin involvement	15 (51.7)	3 (10.3)
Articular involvement	9 (31.0)	3 (10.3)
Renal involvement	5 (17.2)	3 (10.3)
Neuropsychiatric SLE	2 (6.9)	2 (6.9)
Hematological involvement	22 (75.9)	14 (48.3)
SLEDAI score	8 (6–13)	4 (2–7)
Disease activity markers of SLE
C3 (mg/dL)	63 (35–93)	82 (72–100)
C4 (mg/dL)	6.8 (4.8–14.4)	13.1 (7.9–17.3)
Anti-ds DNA Ab (IU/mL)	149 (21.4–345.9)	21.8 (10.0–161.7)
Bone assessment
Biochemical markers
Calcium (mg/dL)	9 (8.4–9.3)	9.2 (8.8–9.5)
Phosphorous (mg/dL)	3.9 (3.5–4.4)	4.3 (3.4–4.8)
Alkaline phosphatase (U/L)	83 (59–109)	80 (56–102)
Parathyroid hormone (pg/mL)	25.1 (23.2–31.5)	27.1 (22.4–45)
25(OH)VitD (ng/mL)	22.3 (17.3–27.1)	20.1 (14.3–28.5)
Radiology
LS BMD z-score	-	-0.9 (-1.8 to 0.1)
Areal LS BMD, g/cm²	-	0.9 (0.8–1.0)
Left femur BMD z-score	-	-1 (-1.8 to -0.3)
Areal left femur BMD (g/cm²)	-	0.8 (0.7–0.9)
VF	-	15 (51.7)
Mild	-	7 (24.1)
Moderate	-	5 (17.2)
Severe	-	3 (10.3)

Values are presented as median (interquartile range) or number (%).

BMI, body mass index; SLE, systemic lupus erythematosus; SLEDAI, Systemic lupus erythematosus disease activity index; Anti-ds DNA Ab, anti-double stranded DNA antibody; 25(OH)VitD, 25-hydroxy vitamin D; LS, lumbar spine; BMD, bone mineral density; VF, vertebral fracture.

Table 2.

Comparison of clinical parameters with respect to a LS BMD z -score of -2.0

Variable	LS BMD z-score > -2.0 (n=22)	LS BMD z-score ≤ -2.0 (n=7)	P-value
Anthropometry
At diagnosis
Height z-score	-0.043 (-0.798 to 0.739)	-1.651 (-1.99 to -0.508)	0.014
Weight z-score	-0.274 (-1.138 to 0.949)	-0.279 (-0.912 to 0.506)	0.470
BMI z-score	-0.038 (-1.498 to -0.892)	0.570 (-0.433 to -1.250)	0.821
Follow-up
Height z-score	-0.504 (-0.861 to 0.719)	-1.843 (-2.364 to -0.736)	0.013
Weight z-score	-0.226 (-1.191 to 1.208)	-0.021 (-0.382 to 0.933)	0.734
BMI z-score	0.045 (-0.823 to 0.957)	0.028 (-0.075 to 1.849)	0.805
Clinical profile
At diagnosis
Skin involvement	11 (50.0)	4 (57.1)	0.742
Articular involvement	6 (27.3)	3 (42.9)	0.438
Renal involvement	4 (18.2)	1 (14.3)	0.812
Neuropsychiatric SLE	2 (9.1)	0 (0)	0.408
Hematological involvement	17 (77.3)	5 (71.4)	0.753
SLEDAI score	10 (5.0–11.5)	8 (7.0–14.5)	0.332
Follow-up
Skin involvement	3 (13.6)	0 (0)	0.302
Articular involvement	1 (4.5)	2 (28.6)	0.069
Renal involvement	3 (13.6)	0 (0)	0.302
Neuropsychiatric SLE	2 (9.1)	0 (0)	0.408
Hematological involvement	2 (9.1)	3 (42.9)	0.742
SLEDAI score	8 (7.0–14.5)	10 (5.0–11.5)	0.664
Flare up	7 (31.8)	5 (71.4)	0.064
Radiology
Follow-up
Initial LS BMD z-score ≤-1.0	6 (27.3)	7 (100)	<0.001
VF
Mild	7 (31.8)	0 (0)	<0.001
Moderate	2 (9.1)	3 (42.9)	<0.001
Severe	0 (0)	3 (42.9)	<0.001

Values are presented as median (interquartile range) or number (%).

LS lumbar spine; BMD, bone mineral density; BMI, body mass index; SLE, systemic lupus erythematosus; SLEDAI, systemic lupus erythematosus disease activity index; VF, vertebral fracture.

Table 3.

Multiple logistic regression analysis of treatment associated factors when the LS BMD z -score is ≤-2.0^*

Variable	LS BMD z-score ≤-2.0^†
	Univariate			Multivariate
	OR (95% CI)	SE	P-value	OR (95% CI)	SE	P-value
Glucocorticoid
Cumulative dose (mg/kg)	1.005 (1.000–1.011)	0.002	0.043	-	-	-
Duration (yr)	3.17 (1.198–8.383)	0.496	0.020	4.486 (1.035–19.445)	0.748	0.045
Hydroxychloroquine (mg/kg)	1.000 (1.000–1.001)	0.001	0.017	-	-	-

LS BMD, lumbar spine bone mineral density; OR, odds ratio; CI, confidence interval; SE, standard error.

^* Three separate multivariate analyses were performed using 2 of the 3 interrelated variables at a time.

^† Adjusted for cholecalciferol intervention.

References

1. Compeyrot-Lacassagne S, Tyrrell PN, Atenafu E, Doria AS, Stephens D, Gilday D, et al. Prevalence and etiology of low bone mineral density in juvenile systemic lupus erythematosus. Arthritis Rheum 2007;56:1966–73.

2. Stagi S, Rigante D. Vitamin D and juvenile systemic lupus erythematosus: lights, shadows and still unresolved issues. Autoimmun Rev 2018;17:290–300.

3. Phang KF, Cho J, Lee W, Mak A. Glucocorticoid-induced osteoporosis in systemic lupus erythematosus. Rheumatol Pract Res 2018;3:2059902118802510.

4. Lilleby V, Lien G, Frey Frøslie K, Haugen M, Flatø B, Førre Ø. Frequency of osteopenia in children and young adults with childhood-onset systemic lupus erythematosus. Arthritis Rheum 2005;52:2051–9.

5. Maggioli C, Stagi S. Bone modeling, remodeling, and skeletal health in children and adolescents: mineral accrual, assessment and treatment. Ann Pediatr Endocrinol Metab 2017;22:1–5.

6. Lee YA, Kwon A, Kim JH, Nam HK, Yoo JH, Lim JS, et al. Clinical practice guidelines for optimizing bone health in Korean children and adolescents. Ann Pediatr Endocrinol Metab 2022;27:5–14.

7. Bultink IEM. Bone disease in connective tissue disease/systemic lupus erythematosus. Calcif Tissue Int 2018;102:575–91.

8. Rizzoli R, Biver E. Glucocorticoid-induced osteoporosis: who to treat with what agent? Nat Rev Rheumatol 2015;11:98–109.

9. Mendoza-Pinto C, Rojas-Villarraga A, Molano-González N, Jiménez-Herrera EA, León-Vázquez ML, Montiel-Jarquín Á, et al. Bone mineral density and vertebral fractures in patients with systemic lupus erythematosus: a systematic review and meta-regression. PLoS One 2018;13:e0196113.

10. Jacobs J, Korswagen LA, Schilder AM, van Tuyl LH, Dijkmans BA, Lems WF, et al. Six-year follow-up study of bone mineral density in patients with systemic lupus erythematosus. Osteoporos Int 2013;24:1827–33.

11. Davidson JE, Fu Q, Rao S, Magder LS, Petri M. Quantifying the burden of steroid-related damage in SLE in the Hopkins Lupus Cohort. Lupus Sci Med 2018;5:e000237.

12. Chen HL, Shen LJ, Hsu PN, Shen CY, Hall SA, Hsiao FY. Cumulative burden of glucocorticoid-related adverse events in patients with systemic lupus erythematosus: findings from a 12-year longitudinal study. J Rheumatol 2018;45:83–9.

13. Gu C, Zhao R, Zhang X, Gu Z, Zhou W, Wang Y, et al. A meta-analysis of secondary osteoporosis in systemic lupus erythematosus: prevalence and risk factors. Arch Osteoporos 2019;15:1.

14. Trapani S, Civinini R, Ermini M, Paci E, Falcini F. Osteoporosis in juvenile systemic lupus erythematosus: a longitudinal study on the effect of steroids on bone mineral density. Rheumatol Int 1998;18:45–9.

15. Nakhla M, Scuccimarri R, Duffy KN, Chédeville G, Campillo S, Duffy CM, et al. Prevalence of vertebral fractures in children with chronic rheumatic diseases at risk for osteopenia. J Pediatr 2009;154:438–43.

16. Burnham JM, Shults J, Weinstein R, Lewis JD, Leonard MB. Childhood onset arthritis is associated with an increased risk of fracture: a population based study using the General Practice Research Database. Ann Rheum Dis 2006;65:1074–9.

17. Valta H, Lahdenne P, Jalanko H, Aalto K, Mäkitie O. Bone health and growth in glucocorticoid-treated patients with juvenile idiopathic arthritis. J Rheumatol 2007;34:831–6.

18. Ward LM, Ma J, Robinson ME, Scharke M, Ho J, Houghton K, et al. Osteoporotic fractures and vertebral body reshaping in children with glucocorticoid-treated rheumatic disorders. J Clin Endocrinol Metab 2021;106:e5195. –207.

19. Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997;40:1725.

20. Aringer M, Costenbader K, Daikh D, Brinks R, Mosca M, Ramsey-Goldman R, et al. 2019 European League Against Rheumatism/American College of Rheumatology classification criteria for systemic lupus erythematosus. Ann Rheum Dis 2019;78:1151–9.

21. Petri M, Orbai AM, Alarcón GS, Gordon C, Merrill JT, Fortin PR, et al. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum 2012;64:2677–86.

22. Silva CA, Avcin T, Brunner HI. Taxonomy for systemic lupus erythematosus with onset before adulthood. Arthritis Care Res (Hoboken) 2012;64:1787–93.

23. The American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes. Arthritis Rheum 1999;42:599–608.

24. Gladman DD, Ibañez D, Urowitz MB. Systemic lupus erythematosus disease activity index 2000. J Rheumatol 2002;29:288–91.

25. Thanou A, Jupe E, Purushothaman M, Niewold TB, Munroe ME. Clinical disease activity and flare in SLE: Current concepts and novel biomarkers. J Autoimmun 2021;119:102615.

26. Yi KH, Hwang JS, Kim EY, Lee JA, Kim DH, Lim JS. Reference values for bone mineral density according to age with body size adjustment in Korean children and adolescents. J Bone Miner Metab 2014;32:281–9.

27. Genant HK, Wu CY, van Kuijk C, Nevitt MC. Vertebral fracture assessment using a semiquantitative technique. J Bone Miner Res 1993;8:1137–48.

28. Fanouriakis A, Kostopoulou M, Alunno A, Aringer M, Bajema I, Boletis JN, et al. 2019 update of the EULAR recommendations for the management of systemic lupus erythematosus. Ann Rheum Dis 2019;78:736–45.

29. LeBlanc CM, Ma J, Taljaard M, Roth J, Scuccimarri R, Miettunen P, et al. Incident vertebral fractures and risk factors in the first three years following glucocorticoid initiation among pediatric patients with rheumatic disorders. J Bone Miner Res 2015;30:1667–75.

30. Costedoat-Chalumeau N, Amoura Z, Hulot JS, Hammoud HA, Aymard G, Cacoub P, et al. Low blood concentration of hydroxychloroquine is a marker for and predictor of disease exacerbations in patients with systemic lupus erythematosus. Arthritis Rheum 2006;54:3284–90.

31. Mok CC, Mak A, Ma KM. Bone mineral density in postmenopausal Chinese patients with systemic lupus erythematosus. Lupus 2005;14:106–12.

32. Lakshminarayanan S, Walsh S, Mohanraj M, Rothfield N. Factors associated with low bone mineral density in female patients with systemic lupus erythematosus. J Rheumatol 2001;28:102–8.

33. Cramarossa G, Urowitz MB, Su J, Gladman D, Touma Z. Prevalence and associated factors of low bone mass in adults with systemic lupus erythematosus. Lupus 2017;26:365–72.

34. Hauser B, Raterman H, Ralston SH, Lems WF. The Effect of anti-rheumatic drugs on the skeleton. Calcif Tissue Int 2022;111:445–56.

35. Ahn MB, Suh BK. Bone morbidity in pediatric acute lymphoblastic leukemia. Ann Pediatr Endocrinol Metab 2020;25:1–9.

36. Cranney AB, McKendry RJ, Wells GA, Ooi DS, Kanigsberg ND, Kraag GR, et al. The effect of low dose methotrexate on bone density. J Rheumatol 2001;28:2395–9.

37. Florén CH, Ahrén B, Bengtsson M, Bartosik J, Obrant K. Bone mineral density in patients with Crohn's disease during long-term treatment with azathioprine. J Intern Med 1998;243:123–6.

38. Zhu TY, Griffith JF, Au SK, Tang XL, Kwok AW, Leung PC, et al. Bone mineral density change in systemic lupus erythematosus: a 5-year followup study. J Rheumatol 2014;41:1990–7.

39. Naka H, Iki M, Morita A, Ikeda Y. Effects of pubertal development, height, weight, and grip strength on the bone mineral density of the lumbar spine and hip in peripubertal Japanese children: Kyoto kids increase density in the skeleton study (Kyoto KIDS study). J Bone Miner Metab 2005;23:463–9.

40. Masip E, Donat E, Polo Miquel B, Ribes-Koninckx C. Bone mineral density in Spanish children at the diagnosis of inflammatory bowel disease. Arch Osteoporos 2021;16:96.