|Year : 2019 | Volume
| Issue : 4 | Page : 853-862
|Bone mineral density and vitamin D status in children with remission phase of steroid-sensitive nephrotic syndrome
Nuran Cetin1, Aylin Gencler1, Ilknur Ak Sivrikoz2
1 Department of Pediatric Nephrology, Faculty of Medicine, Eskisehir Osmangazi University, Eskisehir, Turkey
2 Department of Nuclear Medicine, Faculty of Medicine, Eskisehir Osmangazi University, Eskisehir, Turkey
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|Date of Submission||11-Apr-2018|
|Date of Decision||19-Jun-2018|
|Date of Acceptance||02-Jul-2018|
|Date of Web Publication||27-Aug-2019|
| Abstract|| |
Children with idiopathic nephrotic syndrome are primarily treated with glucocorticoids (GCs), but long-term GC use can lead to undesired side effects. We investigated the bone mineral density (BMD) and 25-hydroxyvitamin D (25-OH D) levels in children with the remission phase of steroid-sensitive nephrotic syndrome (SSNS). This study included 32 patients with SSNS who had not received GC treatment in the last 6 months and a control group of 20 healthy children. Serum levels of calcium, phosphate, alkaline phosphatase, 25-(OH)D, and parathyroid hormone (PTH) were measured. BMD was determined in the lumbar spinal region using dual-energy X-ray absorptiometry (DEXA). Serum 25-(OH)D levels were lower in the SSNS patients than in the healthy children (P <0.05), with 22 patients (68.8%) having Z-scores <-1. The Z-scores were positively correlated with 25-(OH)D levels (r = 0.424, P <0.05). PTH levels were higher in patients with osteoporosis than in patients with Z-scores ≥–1 (P <0.05). Bone mineral content and BMD were positively correlated with the age of diagnosis (P <0.01). Receiver-operating characteristic curve analysis showed that the cutoff value of 25-(OH)D levels for predicting low BMD was 14.67 ng/mL with a sensitivity of 90% and a specificity of 64%. The area under the curve (AUC ± standard error) was 0.868 ± 0.064 (95% confidence interval: 0.742–0.994, P = 0.001). Decreased 25-(OH)D levels and the negative effects of long-term GC treatment on BMD persist in SSNS remission phase. Levels of 25-(OH)D <14.67 ng/mL could predict abnormal DEXA scans in children with SSNS remission phase.
|How to cite this article:|
Cetin N, Gencler A, Sivrikoz IA. Bone mineral density and vitamin D status in children with remission phase of steroid-sensitive nephrotic syndrome. Saudi J Kidney Dis Transpl 2019;30:853-62
|How to cite this URL:|
Cetin N, Gencler A, Sivrikoz IA. Bone mineral density and vitamin D status in children with remission phase of steroid-sensitive nephrotic syndrome. Saudi J Kidney Dis Transpl [serial online] 2019 [cited 2019 Nov 18];30:853-62. Available from: http://www.sjkdt.org/text.asp?2019/30/4/853/265461
| Introduction|| |
Nephrotic syndrome is a glomerular disease characterized by nephrotic range proteinuria, hypoalbuminemia, hyperlipidemia, and edema. Idiopathic nephrotic syndrome (INS) is the most common type of nephrotic syndrome in children, and glucocorticoids (GCs) are the primary treatment. Steroid dependence is observed in 20%–30% of children with INS. The long-term use of GCs is associated with negative side effects such as growth retardation, obesity, osteoporosis, and cataract.
Bone mineralization majorily occurs during childhood and adolescence. Peak bone mass and bone mineral density (BMD) are affected by factors such as age, weight, height, and the exposure to drugs and other environmental factors. BMD begins to decrease two weeks after the initiation of GC treatment. Osteoblast inhibition causes GC-induced osteoporosis in the chronic phase of the disease. High doses of GC lead to decreases in the lumbar spine area (LS-BMD) during the early treatment period of children with INS. Subsequently, LS-BMD decreases later during intermittent GC therapy to manage INS symptoms.
Vitamin D plays an important role in bone development. The levels of 25-hydroxyvitamin D (25-OH D) indicate a patient’s vitamin D status and are associated with BMD in children and adolescents. Low concentrations of 25-(OH)D have been reported in patients in NS relapse phase, but, only limited. Information is available on the serum 25-(OH)D levels and bone health of patients in the remission phase of steroid-sensitive nephrotic syndrome (SSNS).
In this study, we aimed to investigate the serum 25-(OH)D levels and bone health of children with SSNS who had not received GC treatment during the previous six months. We also explored whether there was a relationship between BMD and the dose and/or duration of GC treatment.
| Materials and Methods|| |
This study analyzed data from children with INS who were seen at our department, between December 1, 2009, and December 1, 2016. Information on the course of the disease, the duration of GC therapy (months), and the cumulative steroid dose (mg/m2) was obtained from the patients’ medical records.
The patients were classified according to their response to GC treatment. Patients who achieved remission during an eight-week GC course were defined as having SSNS. Patients with two or more relapses within six months of the initial response or with four or more relapses in any 12-month period were classified as having frequently relapsing nephrotic syndrome (FRNS). A diagnosis of steroid-dependent nephrotic syndrome was made for patients with two consecutive relapses during the tapering of the GC dose or within 14 days after GC withdrawal. The absence of remission within eight weeks of GC treatment was defined as steroid resistance.
The data from the children with SSNS were subjected to further analysis. Children with SSNS who had not received GC treatment in the last six months were included in the study. We excluded patients who had received GC treatment at the beginning of the study. In addition, patients with steroid-resistant NS and signs of hypocalcemia or any other systemic disease known to produce nephrotic syndromes were not included in the present study. In our Pediatric Nephrology Clinic, treatment with 600 mg of elementary calcium and 400 IU of Vitamin D3 is routinely initiated in SSNS patients receiving GC treatment, but the selected patients did not receive elementary calcium or Vitamin D3 during this study.
Height measurements were taken with the child standing without shoes. Body weights were measured using a digital scale. Short stature was defined as a height more than two standard deviations (SDs) below the mean for age and sex. Body mass index (BMI) was calculated as weight divided by height squared. Obesity was defined as a BMI at or above the 95th percentile for children and teens of the same age and sex. Delayed growth and puber-tal development contribute to a low bone mass for age or sex; therefore, patients with growth retardation or delayed puberty were excluded from this study.
Routine laboratory techniques were used to measure serum creatinine, blood urea nitrogen, phosphorous (P), calcium (Ca), parathyroid hormone (PTH), and alkaline phosphatase (ALP) levels and to perform urine biochemistry analysis. Blood samples were obtained in the morning after an overnight fast of at least 12 h as ALP levels can increase after food ingestion. The reference ranges of serum Ca, P, PTH, and ALP levels were 8.6–10.2 mg/dL, 2.7–4.5 mg/dL, 15–65 pg/mL, 0–187 U/L, respectively.
Serum 25-(OH)D levels were measured using a radioimmunoassay method and classified according to the Endocrine Society Clinical Practice Guidelines (<20 ng/mL, deficiency; 21–29 ng/mL, insufficiency; and >30 ng/mL, adequate levels). BMD (g/cm2), bone mineral content (BMC, g), and BMD Z-scores were determined using dual-energy X-ray absorp-tiometry (DEXA) of the lumbar spine (L1-4) performed with thin-mode scans (QDR 4500 X-ray Bone Densitometer, Hologic Inc, 590 Lincoln ST, Waltham, MA, 02154, USA) in all patients. Low BMD was defined with a BMD Z-score according to age, gender, and body size. Osteopenia was defined as a Z- score <–1.0, and osteoporosis was defined as a Z-score <–2.5.
This study was approved by the local ethics committee. Written informed consent was obtained from the parents or legal guardians of all participants, according to the Declaration of Helsinki.
| Statistical Analysis|| |
Statistical analyses were performed using Statistical Package for the Social Sciences (SPSS) version 11.0 (SPSS Inc., Chicago, IL, USA). Values were expressed using a mean and SD for continuous variables and using an interquartile range (IQR) for qualitative variables. The Shapiro–Wilk test was used to determine the normality of the data. Means were compared using the independent sample t-test for normally distributed data. Comparison of the nonnormally distributed data was performed using the Mann–Whitney U-test. Correlations between variables were evaluated using the Pearson’s or Spearman’s test as appropriate. P <0.05 was considered statistically significant. Qualitative variables were compared using the Chi-square test. Receiver-operating characteristic (ROC) analysis was used to determine the cutoff values and the sensitivity/specificity of 25-(OH)D levels for the prediction of low BMD.
| Results|| |
Out of 38 children with INS, 32 SSNS patients were included in this study. Six patients who received GC treatment at the beginning of the study were excluded from the study. Twenty healthy children were included in the control group. The age, gender, and BMI data were similar between the patient and control groups (P >0.05). Serum 25-(OH)D levels were lower in patients with SSNS than in the healthy controls (16.1 ± 8.25 ng/mL vs. 20.8 ± 6.34 ng/mL, respectively, P = 0 0.034).
Of the 32 patients with SSNS, 22 (68.8%) were male, and the median age at the onset of the disease was three years (IQR 2.3–7). Half of the SSNS patients (16, 50%) had FRNS, whereas the other 16 (50%) patients had infrequent relapse nephrotic syndrome (IFRNS). The number of attacks, the duration of the disease, the cumulative steroid dose, and the duration of GC treatment were higher in patients with FRNS than in those with IFRNS. The demographic characteristics of the patients with FRNS and IFRNS are shown in [Table 1].
|Table 1: Demographic characteristics of the patients with IFRNS and FRNS.|
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The serum levels of 25-(OH)D were lower than 30 ng/mL in 30 (93.8%) SSNS patients [deficiency: 23 (76.7%) patients, insufficiency: 7 (23.3%) patients]. Serum 25-(OH)D levels were similar between the IFRNS and FRNS patients (16.4 ± 9.09 ng/mL vs. 15.9 ± 7.61 ng/mL, P >0.05). However, the FRNS patients had lower 25-(OH)D levels than the healthy children (15.9 ± 7.61 ng/mL vs. 20.8 ± 6.34 ng/mL, respectively, P = 0.043, [Table 2]). Serum 25-(OH)D levels did not correlate with the number of attacks, the cumulative steroid dose, the duration of GC treatment, and the duration of the disease (P >0.05, [Table 3]).
|Table 3: The correlation coefficients of serum 25-(OH)D levels and DEXA scan data.|
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The correlations of BMC and BMD with the various parameters are shown in [Table 4]. BMC and BMD were positively correlated with the age of diagnosis (r = 0.69, P = 0.000; r = 0.51, P = 0.004, respectively). However, neither BMC nor BMD correlated with serum PTH levels, the cumulative GC dose, the duration of GC treatment, or the number of attacks (P >0.05). In addition, the BMD and BMC values of patients with vitamin D deficiency and insufficiency were compared. The BMD and BMC values were lower for the patients with vitamin D deficiency than for those with insufficiency (0.6 ± 0.12 g/cm2 vs. 0.8 ± 0.23 g/cm2, P = 0.030; 27.9 ± 9.55 g vs. 43.3 ± 21.33 g, P = 0.013, respectively).
|Table 4: The comparison of features of the patients with low and normal Z-scores.|
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In the study group, 22 (68.8%) patients had Z-scores <-1 [13 (40.6%) patients with osteopenia and nine (28.1%) patients with osteoporosis]. Serum 25-(OH)D levels were lower in patients with osteopenia and osteoporosis than in the patients with Z-scores ≥-1 (12.1 ± 5.76 ng/mL vs. 23.2 ± 5.86 ng/mL, P = 0.000; 14.3 ± 9.18 ng/mL vs. 23.2 ± 5.86 ng/mL, P = 0.022, respectively, [Table 4]). Z- scores were positively correlated with serum 25-(OH)D levels (r = 0.424, P = 0.016). ROC curve analysis showed that the cutoff level of 25-(OH) D for predicting low BMD was 14.67 ng/mL, with a sensitivity of 90% and a specificity of 64%. The area under the curve (AUC ± standard error) was 0.868 ± 0.064 (95% confidence interval: 0.742–0.994, P = 0.001).
PTH levels were similar for osteopenic and osteoporotic patients (P >0.05). The osteoporosis patients had higher PTH levels compared to patients with Z-scores ≥–1 [57 (38–69) pg/mL vs. 35.5 (24.11–51.83) pg/mL, P = 0.027, [Table 4]. In addition, Z-scores were inversely correlated with serum PTH levels (r = -0.44, P = 0.012). The duration of the disease was longer in patients with osteoporosis than in patients with Z-scores ≥–1 (8.8 ± 2.6 years vs. 7.5 ± 3.85 years, respectively, P = 0.049). The number of attacks, the cumulative GC dose, and the age of diagnosis were similar between the patients with low and normal Z-scores (P >0.05, [Table 4]).
Next, we investigated the effects of BMI on serum 25-(OH)D levels and DEXA values. Out of the 32 SNSS patients, five (15.6%) were obese. The 25-(OH)D levels and Z-scores were similar between the obese and nonobese patients (18.5 ± 6.01 ng/mL vs. 15.9 ± 8.01 ng/mL, P = 0.248, and -1.1 (–1.8–0.4) vs. -1.9 (–2.75–−0.9), P = 0.104). There was no difference in the mean BMI between the IFRNS and FRNS subgroups (P >0.05). We evaluated the correlations between BMI, BMC, BMD, and Z-scores. There were no significant correlations between BMI and DEXA values [Table 3]. In addition, there was no BMI difference between patients with low and normal Z-scores [Table 4].
| Discussion|| |
The results of our study showed that serum 25-(OH)D levels were lower in patients in the FRNS remission phase than in the healthy controls, and that there was a positive relationship between 25-(OH)D levels and Z-scores. Patients with 25-OH D deficiency had lower BMC and BMD. Serum 25-(OH)D levels and Z-scores did not correlate with the number of attacks, the cumulative steroid dose, or the duration of GC treatment.
Vitamin D is the principal regulator of calcium homeostasis. In recent years, the rate of 25-(OH)D deficiency has increased among the healthy population. Previously published reports have shown that transient 25-(OH)D deficiency was observed in children during NS relapse periods. The loss of Vitamin D-binding protein in the urine is responsible for the development of 25-(OH)D deficiency in children during the NS active phase. There have been conflicting reports on the serum 25- (OH)D levels in children during the NS remission phase. Freundlich et al showed that serum 25-(OH)D levels improved during the NS remission phase. Banerjee et al found that serum 25-(OH)D levels were lower within three months of relapse, but that the levels were similar between the controls and patients with longer remission periods. In our study, serum 25-(OH)D levels were <30 ng/mL in most of the children in the SSNS remission phase. However, the average serum 25-(OH)D levels of the control group were also <30 ng/mL. Serum 25-(OH)D levels were similar between the IFRNS patients and the healthy controls, but there was a significant difference between the patients in the FRNS remission phase and the healthy controls. The decreased 25-(OH)D levels in the IFRNS patients may have simply reflected the abnormalities in 25- (OH)D levels that are expected in the general pediatric population. The reduction in the 25- (OH)D levels could not be explained by disease activity in the FRNS remission-phase patients. Furthermore, serum 25-(OH)D levels did not correlate with the number of attacks, the cumulative steroid dose, or the duration of GC treatment. Reduced sun exposure or alterations in eating habits during relapses could have influenced serum 25-(OH)D levels. Further studies are needed to determine the underlying causes of the reduced 25-(OH)D levels in the FRNS remission-phase patients.
Osteoporosis is one of the most serious side effects of long-term GC therapy. BMD begins to decline two weeks after GC treatment has started, and the decrease in bone mass develops during the first three to six months., The GC effect on osteoblasts during the chronic phase of the disease is a primary cause of GC-associated osteoporosis. There are conflicting reports about whether the GC effects on bone loss are permanent in children with SSNS. Several studies have shown that GCs lead to a decrease in BMD Z-scores in SSNS patients and that BMD Z-scores are correlated with the cumulative GC dose. Leonard et al reported that many SSNS patients had normal BMD, and that the cumulative GC dose did not have an effect on BMC. Another study determined that children with SSNS had persistent bone abnormalities that continued into adulthood. Prentice et al showed that GC-associated reduction in bone formation was transient, and that an increase in BMC was observed during the NS remission phase. Our results may suggest that the negative GC effects on bone loss persist and may even be permanent in children in the SSNS remission phase, even after cessation of GC treatment. All the patients in our study with SSNS had received GC treatment for at least 12 weeks. Thus, GC exposure >12 weeks may be a principal risk factor for osteoporosis rather than the cumulative GC dose.
Childhood and adolescence are critical periods for bone formation. Vitamin D has beneficial effects on bone mineralization. Decreased serum Vitamin D levels will have negative effects on skeletal mineralization due to reduced intestinal Ca absorption. GCs also decrease intestinal Ca absorption and increase urinary Ca losses. Hypocalcemia and decreased vitamin D levels lead to elevated PTH levels, which, in turn, lead to decreased BMD due to increased bone mineral resorption. El-Mashad et al showed that INS patients receiving high doses of GCs had elevated PTH levels, and that GCs had a negative effect on bone mineralization. In our study, Z-scores were positively correlated with serum 25-(OH)D levels and were inversely correlated with serum PTH levels. Serum Ca levels were normal in all the SSNS patients and were similar in patients with normal and reduced BMD, indicating that the Ca balance was preserved at the expense of skeletal strength. Serum 25-OH D and PTH levels could be markers of bone metabolism for patients in the SSNS remission phase.
BMD and BMC values do not reflect the true volumetric bone density and should be compared to healthy growing children (controls). BMD values are routinely used for the diagnosis of osteoporosis in adults, but DEXA values are reported as a percentile or a standard deviation score in children. Our study evaluated the relationship between BMC, BMD, and other parameters. BMC and BMD values were positively correlated with the age of diagnosis. They were also lower in patients with Vitamin D deficiency than in patients with insufficiency. Steroid exposure at an earlier age and lower Vitamin D levels had a negative effect on both BMC and BMD. Further studies are needed to confirm whether BMC and BMD values are biomarkers of bone health in children with SSNS.
The obesity prevalence during GC treatment for SSNS has been reported at 35%–43% during GC treatment in SSNS, but body weight generally reduced after GC cessation.,, A relationship has been found between BMD, body weight, and BMI in children and adolescents. Several studies have reported increased bone mass and density in obese children, whereas others reported reduced values when compared to children with normal weights.,,, Moore et al reported lower serum levels of 25-(OH) D in obese children. Our results showed that the frequency of obesity and BMI was similar between the healthy controls and the SSNS patients who had no GC treatment in the previous six months. In addition, BMI did not have an effect on DEXA values or 25-(OH)D levels. We did not compare height, weight, and BMI with patient data prior to starting GC treatment because the anthropometric data of edematous patients do not provide accurate information. Nevertheless, our findings suggest that abnormalities in bone mineralization, regardless of BMI, persist in SSNS patients after cessation of GC treatment.
There are some limitations to our study. Seasonal variations in 25-(OH)D levels, exposure to sunlight, and eating habits were not included in our analysis. There was no information on previous Ca and/or Vitamin D supplementation taken by the patients. In addition, we did not perform serial measurements of bone density and serum 25-(OH)D levels.
Our study suggests that decreased 25-(OH)D levels and abnormalities in bone mineralization may persist in children during the SSNS remission phase also. Clinicians should be aware that children could have bone mineralization disorders even after GC treatment has been completed. Serum 25-(OH)D levels <14.67 ng/mL could be a predictor of abnormal DEXA scans for children in the SSNS remission phase. Prospective studies with larger sample sizes are needed to confirm these results.
Conflict of interest: None declared.
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Department of Pediatric Nephrology, Faculty of Medicine, Eskisehir Osmangazi University, Eskisehir
[Table 1], [Table 2], [Table 3], [Table 4]
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