Abstract

Background. We previously have demonstrated that children with idiopathic nephrotic syndrome (INS) are at risk of metabolic bone disease (MBD). In this study, we report the longitudinal follow-up of these children and the role of calcium and vitamin D supplements.

Methods. We prospectively studied 100 consecutive children with INS. They were treated with prednisone. All were subjected to a baseline clinical, biochemical and radiological evaluation. They were initiated on calcium (500 mg/day) and vitamin D3 (200 IU/day) supplements, followed by a repeat assessment. The primary outcome measure was the Δz score (difference between the initial and final z scores) on dual energy X-linked absorptiometry (DEXA). A univariate and multivariate analysis using stepwise linear regression was performed for factors predictive of an improved Δz score.

Results. Of the 88 children that completed the study, the majority (n = 54) had improved bone mineral density (BMD) at the spine, and another 25 children had stable BMD on calcium and vitamin D3 supplements. The mean spinal BMD values were significantly better on follow-up (0.607±0.013 g/cm2) as compared with baseline values (0.561±0.010 g/cm2) (P<0.0001). The interval between initial and follow-up assessment was 1.5±0.07 years. Children who were on these supplements (n = 73) had a significantly improved z score as compared with those who did not receive them (n = 15) (P = 0.008). On multivariate analysis, the factors predictive of an improved z score were: younger age (P<0.0001), calcium and vitamin D3 supplement (P<0.0001), greater dietary calcium intake (P = 0.022) and lower interval steroid dose (P = 0.001).

Conclusions. Children with greater steroid doses were likely to have low BMD on follow-up. Calcium and vitamin D supplements may help in improving BMD in children with INS.

Introduction

There is still conflicting evidence on the risk of low bone mass in children with nephrotic syndrome. We have demonstrated previously that children with idiopathic nephrotic syndrome (INS) are at risk for metabolic bone disease (MBD) [1]. There are a few other studies in a small number of patients to suggest that patients with nephrotic syndrome are indeed at risk of low bone density [2–4]. In contrast, in a recent study, Leonard et al. report that children receiving corticosteroids (CCS) do not appear to have deficits in the bone mineral content (BMC) [5]. Most of this evidence to date is cross-sectional in nature.

There are also data to suggest that vitamin D plus calcium is superior to no therapy or calcium alone in the management of corticosteroid-induced osteoporosis (COP) in kidney transplant patients [6,7]. There is no study to date which has evaluated the role of these supplements in INS.

Hence this study was conducted to evaluate (i) the longitudinal changes in bone mineral density (BMD) in children with nephrotic syndrome; and (ii) the role of calcium and vitamin D supplements in the prevention of MBD.

Methods

We prospectively studied 100 consecutive children with INS. Informed consent was obtained and they were all subjected to a detailed history and physical examination for clinical evidence of disturbances in calcium metabolism and MBD, i.e. history of bone pain, fractures or spasms of hands and feet. In addition, the following biochemical tests were carried out to confirm the diagnosis of nephrotic syndrome: serum creatinine, total protein, albumin, cholesterol, triglycerides and urinary routine microscopy, and urine protein and creatinine ratio in a spot sample. We included only those children who fulfilled the International Study of Kidney Disease in Children (ISKDC) criteria for the diagnosis of nephrotic syndrome as defined in our earlier study and who had normal renal functions [glomerular filtration rate (GFR) >90 ml/min/1.73 m2] [1,8]. Children were excluded if (i) they required furosemide/thiazide diuretics for control of oedema during the study period; (ii) they had received bisphosphonates; (iii) they had received cyclosporine therapy; (iv) there was clinical evidence of malnutrition; or (v) they did not have a follow-up serum calcium phosphorus, alkaline phosphatase or BMD assessment.

These children were treated with prednisone as per the protocol described in our earlier study [8]. All patients maintained a steroid diary, and the dose of prednisone in between the two BMD estimations (interval steroid dose) was recorded. An estimate was also made of the total dose of prednisone received by them from their previous case records.

The dietary calcium and protein intake and the total calcium intake were calculated as in our earlier study. A baseline recording of the height and weight was carried out. They were then subjected to the following biochemical tests for evidence of MBD: serum calcium, phosphorus, alkaline phosphatase and intact parathyroid hormone (PTH) levels as well as a baseline bone densitometry. All children were prescribed a fixed dose combination of 500 mg of calcium carbonate (200 mg elemental calcium) and 200 IU of vitamin D3 as a single tablet to be taken on an empty stomach the first thing in the morning. This dose was chosen empirically, as it was half the dose that was found to be beneficial in adults with rheumatoid arthritis [9]. They were followed monthly for the first 3 months and thereafter every 3 months. At each visit, they were assessed for their height, weight and status of nephrotic syndrome. A detailed interview was also conducted to ensure compliance with the calcium and vitamin D supplement. A repeat follow-up assessment was done for renal functions (serum creatinine and GFR), biochemistry (serum calcium, phosphorus and alkaline phosphatase) and bone densitometry between 6 and 12 months after the initial evaluation.

Bone densitometry estimation was done by dual energy X-linked absorptiometry (DEXA) of the lumbar spine [antero-posterioral (AP) and lateral] and whole body using the methodology described in our earlier study [1]. The bone density scans for each patient were analysed by one person who was unaware of the patient's dose of corticosteroid and treatment group. The primary outcome measure was the Δz score. This was calculated as the difference between the initial and the final z scores measured on the AP view of the lumbar spine (L1–L4). The precision error of BMD estimation at the spine has been estimated to be 0.01 g/cm2. The least significant change (LSC) at the 95% confidence interval (CI) is 2.77 times the SD. Based on this, the LSC was estimated to be 2.77 × 0.01 g/cm2 = 0.03 g/cm2. Based on the change in BMD values at the spine (AP view) in these children, a deterioration in bone density was defined as a change in BMD value on the AP view of the lumbar spine (L1–L4) spine greater than −0.03 g/cm2 and an improvement defined as a change in percentage z score by more than +0.03 g/cm2. Children with BMD values between −0.03 and +0.03 g/cm2 were considered to have stable bone density. The study was approved by the Institute Ethics Board.

Statistical analysis

The statistical analysis was performed using the SPSS 9.0 statistical analysis software (Chicago, IL). We compared the different biochemical and radiological parameters in the group of patients before and after treatment using the paired t-test (two-tailed), χ2 test and Fischer's exact test. Next we also studied the correlation of the various clinical, biochemical and radiological parameters for the entire study group with the BMD Δz score. For continuous variables, we used the Pearson correlation coefficient method for normal data and the Spearman's coefficient for data that were not normally distributed. Subsequently, a multivariate analysis was done to evaluate factors predictive of an improvement in the z score. The variables with a P-value of <0.05 were then entered into a stepwise linear regression model. The model with the greatest R2-value was finally considered. As a separate subanalysis, the 15 children who had stopped calcium supplements were compared with the rest of the 73 children who continued calcium and vitamin D supplements. Data are expressed as the mean±SEM. A P-value of <0.05 was considered as significant.

Results

We recruited 100 consecutive children with INS into our study and subjected them to a baseline assessment. These results have been reported by us earlier [1]. Of the 100 children, 12 were excluded as they did not have a follow-up serum calcium, phosphorus, alkaline phosphatase or a BMD assessment. We report here the prospective follow-up results on the remaining 88 children.

There were 75 boys and 13 girls, and the mean age at initial BMD determination was 9.03±0.45 years. On the first follow-up visit, 15 of the 88 children admitted not to have initiated the supplements at all. Since all of them were asymptomatic, they were not restarted on these supplements and were followed-up as a control group. The mean age at follow-up BMD determination was 10.5±0.46 years. The interval between initial and follow-up assessment was 1.5± 0.07 years. A repeat clinical evaluation at the end of the study period revealed that none of the patients developed pathological fractures. The follow-up serum calcium and alkaline phosphatase values in the entire study group were significantly better compared with the baseline values (Table 1). The mean prednisone dose between the BMD studies (interval prednisone dose) in the study group was 5250±280 mg. Of the 88 children, 27 were infrequent relapsers, 11 were frequent relapsers, 37 were steroid dependent and 13 were steroid non-responders. The total dose of prednisone received by them was 11 509±1264 mg (range 790–56 880 mg).

Table 1.

Comparison of biochemical and radiological values in the study group (n = 88) before and after calcium and vitamin D supplements

 Baseline Follow-up P-value 
Serum Ca (mEq/l) 8.5±0.10 8.7±0.07 0.007 
Serum P (mEq/l) 4.8±0.09 4.7±0.08 0.416 
Serum alkaline phosphatase (IU/ml) 317±18 270±9.0 0.002 
BMD whole body (g/cm20.799±0.010 0.830±0.010 0.000 
BMD mid spine (lateral) 0.526±0.011 0.546±0.010 0.054 
BMD spine AP (g/cm20.561±0.013 0.607±0.013 0.000 
% z score 81.6±12.3 83.6±1.4 0.05 
 Baseline Follow-up P-value 
Serum Ca (mEq/l) 8.5±0.10 8.7±0.07 0.007 
Serum P (mEq/l) 4.8±0.09 4.7±0.08 0.416 
Serum alkaline phosphatase (IU/ml) 317±18 270±9.0 0.002 
BMD whole body (g/cm20.799±0.010 0.830±0.010 0.000 
BMD mid spine (lateral) 0.526±0.011 0.546±0.010 0.054 
BMD spine AP (g/cm20.561±0.013 0.607±0.013 0.000 
% z score 81.6±12.3 83.6±1.4 0.05 

Data are the mean±SEM.

On evaluating the change in BMD values at the spine (AP view) in the entire group of 88 children, we observed that 54 children (61%) showed an improved BMD on calcium and vitamin D supplements, while 27 (31%) children showed a stable BMD despite prednisone therapy. There was deterioration in the Δz scores in only seven out of 88 children. The mean spinal BMD values in the entire group (n = 88) were significantly better at the end of the study period (0.607±0.013 g/cm2) as compared with the baseline values (0.561±0.01 g/cm2) (P<0.0001). There was a corresponding improvement in the mean baseline percentage z scores, whole body bone density values and the lateral spine bone density values (Table 1).

On univariate analysis, we observed that the BMD Δz score correlated significantly with age at initial BMD (P<0.00001), the dietary calcium intake (P = 0.050), the calcium and vitamin D supplement (P<0.00001), the interval steroid dose (P<0.00001), the baseline BMD z score (P = 0.001) as well as the age at follow-up BMD study (P = 0.040). There was no correlation with the age at onset of nephrotic syndrome, clinical features, gender distribution, the initial serum albumin, calcium, phosphorus, alkaline phosphatase and PTH, or the follow-up serum calcium, phosphorus and alkaline phosphatase values. There was also no correlation of the BMD Δz score with the time interval between BMD studies in these patients.

In the second stage, a multivariate analysis was done to identify factors predictive of an improvement in BMD Δz score on follow-up. We observed that the only factors which significantly correlated with an improved BMD Δz score were: younger age at BMD study (P<0.0001), calcium and vitamin D supplement (P<0.0001), greater dietary calcium intake (P = 0.022) and lower interval steroid dose (P = 0.001) (R = 0.712) (Table 2).

Table 2.

Multivariate analysis for factors predictive of Δ BMD z score

Predictors Unstandardized coefficients
 
 Standardized coefficients
 
t Significance 95% CI
 
 
 SE β   Upper Lower 
(Constant) −0.261 0.301  −0.866 0.389 −0.860 0.339 
Initial z score −0.435 0.075 −0.500 −5.781 0.000 −0.584 −0.285 
Calcium and vitamin D supplement 0.003 0.001 0.356 4.400 0.000 0.001 0.004 
Age at BMD −0.073 0.018 −0.337 −4.122 0.000 −0.109 −0.038 
Steroid dose per year 0.000 0.000 −0.274 −3.342 0.001 0.000 0.000 
Dietary calcium intake 0.001 0.000 0.191 2.340 0.022 0.000 0.001 
Predictors Unstandardized coefficients
 
 Standardized coefficients
 
t Significance 95% CI
 
 
 SE β   Upper Lower 
(Constant) −0.261 0.301  −0.866 0.389 −0.860 0.339 
Initial z score −0.435 0.075 −0.500 −5.781 0.000 −0.584 −0.285 
Calcium and vitamin D supplement 0.003 0.001 0.356 4.400 0.000 0.001 0.004 
Age at BMD −0.073 0.018 −0.337 −4.122 0.000 −0.109 −0.038 
Steroid dose per year 0.000 0.000 −0.274 −3.342 0.001 0.000 0.000 
Dietary calcium intake 0.001 0.000 0.191 2.340 0.022 0.000 0.001 

Dependent variable Δz.

R-value for the model = 0.712.

F = 16.839, P = 0.000 (ANOVA).

A separate subgroup analysis was done, comparing the group of 15 children (group I) who had discontinued the supplements right at the onset with the rest of the 73 (group II) children who continued on them. There was no significant difference between the two groups regarding the mean age of onset, age at BMD, gender distribution, dietary calcium intake, steroid dose/year, age at follow-up BMD, as well as the initial serum calcium, phosphorus and alkaline phosphates and the PTH values (Table 3). We observed that at the end of the study, children in group II had a significantly improved Δz score compared with those in group I (P = 0.008).

Table 3.

Comparison of demographic, clinical and biochemical values in patients not receiving (group I) or receiving (group II) calcium and vitamin D supplements

 Group I (n = 15) Group II (n = 73) P-value 
M:F 14:1 61:12 0.453 
Mean age of onset (years) 6.5±1.2 5.3±0.55 0.39 
Mean age at BMD (years) 9.6±1.04 8.9±0.5 0.56 
Dietary calcium intake (mg/day) 696.7±73.5 723.3±35.2 0.754 
Total calcium intake (mg/day) 696.6±73.5 964.5±336.7 0.005 
Symptoms 0.17 
Height (cm) 123.6±4.9 119.1±2.7 0.487 
Weight (kg) 25.4±2.5 29.7±2.9 0.515 
Interval steroid dose (mg) 5466±774 5160±295 0.684 
Serum albumin (g/l) 3.76±0.15 3.5±0.10 0.288 
Serum Ca (mEq/l) 8.5±0.20 8.5±0.11 0.869 
Serum P (mEq/l) 4.7±0.25 4.8±0.09 0.869 
Serum alkaline phosphatase (IU/l) 370±38 306±21 0.196 
PTH (pg/ml) 17.1±1.01 17.8±0.71 0.678 
Follow-up Ca (mEq/l) 8.7±0.14 8.7±0.08 0.958 
Follow-up P (mEq/l) 4.8±0.18 4.72±0.09 0.661 
Follow-up serum alkaline phosphatase (IU/l) 307.9±24.5 261±9.8 0.06 
Follow-up serum albumin (g/l) 3.9±0.18 3.8±0.12 0.29 
Age at follow-up BMD (years) 10.9±1.02 10.45±0.51 0.701 
Initial z score −1.578±0.029 −1.571±0.015 0.982 
Follow-up z score −1.960±0.260 −1.273±0.132 0.03 
ω z score −0.382±0.116 0.298±0.111 0.008 
 Group I (n = 15) Group II (n = 73) P-value 
M:F 14:1 61:12 0.453 
Mean age of onset (years) 6.5±1.2 5.3±0.55 0.39 
Mean age at BMD (years) 9.6±1.04 8.9±0.5 0.56 
Dietary calcium intake (mg/day) 696.7±73.5 723.3±35.2 0.754 
Total calcium intake (mg/day) 696.6±73.5 964.5±336.7 0.005 
Symptoms 0.17 
Height (cm) 123.6±4.9 119.1±2.7 0.487 
Weight (kg) 25.4±2.5 29.7±2.9 0.515 
Interval steroid dose (mg) 5466±774 5160±295 0.684 
Serum albumin (g/l) 3.76±0.15 3.5±0.10 0.288 
Serum Ca (mEq/l) 8.5±0.20 8.5±0.11 0.869 
Serum P (mEq/l) 4.7±0.25 4.8±0.09 0.869 
Serum alkaline phosphatase (IU/l) 370±38 306±21 0.196 
PTH (pg/ml) 17.1±1.01 17.8±0.71 0.678 
Follow-up Ca (mEq/l) 8.7±0.14 8.7±0.08 0.958 
Follow-up P (mEq/l) 4.8±0.18 4.72±0.09 0.661 
Follow-up serum alkaline phosphatase (IU/l) 307.9±24.5 261±9.8 0.06 
Follow-up serum albumin (g/l) 3.9±0.18 3.8±0.12 0.29 
Age at follow-up BMD (years) 10.9±1.02 10.45±0.51 0.701 
Initial z score −1.578±0.029 −1.571±0.015 0.982 
Follow-up z score −1.960±0.260 −1.273±0.132 0.03 
ω z score −0.382±0.116 0.298±0.111 0.008 

Data are expressed as the mean±SEM.

Discussion

Our study reveals that in the 88 children that completed the study, the mean spinal BMD values (AP spine L1–L4) were significantly better at the end of the study period (0.607±0.013 g/cm2) compared with the baseline values (0.561±0.01 g/cm2) (P<0.0001). We observed that the vast majority (92%) of children showed an improvement/stabilization in their BMD z scores and there was deterioration in only seven out of 88 children. None of the patients developed pathological fractures.

BMD values are influenced by age, height, gender and nutritional status. Thus z scores (matched for age) are the best way to evaluate BMD in children [10]. In the absence of normative data in the Indian children, z scores were calculated based on comparison with normal values for age (corrected for height), from the manufacturer's database as in our earlier study [1]. Since the same technique, machine and the database were used for the initial as well as the follow-up study, this is unlikely to influence findings. The effect of gender on BMD is also less likely, as this becomes important only beyond 16 years of age. In our study, only three children were older than 16 years at their BMD evaluation.

A subgroup comparison was done of the longitudinal follow-up BMD data of the 15 patients (group I) who were off these supplements, with the rest of the 73 children who continued them (group II). We observed that children in group II had a significantly improved follow-up z score compared with group I, who showed a deterioration in their follow-up z scores (Table 3). Although this was not a randomized control group and the numbers were smaller, it does demonstrate that the calcium and vitamin D supplements are beneficial in children with INS.

Decreased BMD has been described in a wide spectrum of paediatric disorders ranging from juvenile rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus therapy, leukaemia and asthma, as well as after bone marrow transplant, cardiac transplant, liver transplant and kidney transplant [11–13]. Steroids are perhaps the only common denominator in this wide variety of paediatric disorders. A recent case–control study involving >20 000 children receiving systemic CCS found an increased risk of fracture [14]. Daily prednisone doses of ≥7.5 mg cause significant bone loss and a doubling in the risk of fracture; however, even lower doses or inhaled steroids may also induce bone loss [6]. Steroids in short courses and high doses continue to be the first line of therapy in patients with INS. The aetiology of this bone loss is multifactorial. There is direct inhibition of the bone-forming osteoblast and an effect on overall calcium balance. Reduced bone formation may be a consequence of reduction of osteoblast differentiation and an inhibition of the synthesis of osteoid by these cells [15]. CCS also decrease intestinal absorption of calcium and its reabsorption by the renal tubule. The resulting secondary hyperparathyroidism leads to increased osteoblast activity and increased bone resorption [16].

In a previous study, we observed that 29 of the 100 children (29%) had low bone density for chronological age as per the ISCD guidelines [1,10]. Even in the current study, the mean initial z score was low (−1.6), presumably secondarily to the prior prednisone therapy. There are preliminary data from other studies to support this [2–4]. In contrast, Leonard et al. in a recent study report that children receiving CCS do not appear have deficits in the BMC [5]. However, they did find a lower BMC at the spine after correction for body mass index. The earliest changes of CCS-induced bone loss are indeed seen in the lumbar spine because of its high BMC [13]. There was also no information on the dietary calcium intake, previous calcium and/or vitamin D therapy or data on the correlation between the BMC and the CCS dose. It is possible that a greater dietary intake of calcium and vitamin D in their patients minimized the effects of steroids. Moreover, 38% of the children in their study were obese, which could also have affected the results. Obese patients have less bone for a given body weight than those with normal body weight and also more fat mass. This in turn could be due to lower physical activity [17]. Another major limitation of this study was that the observations were cross-sectional in nature.

It is likely that these children will fail to achieve their peak bone mass (which is a key determinant of the lifetime risk of osteoporosis) and are at risk for fractures later on during their lifetime. As the foundation for skeletal health is established so early in life, osteoporosis prevention is best achieved by optimizing gains in bone mineral throughout childhood and adolescence. We observed that the factors which were significantly predictive of an improvement in BMD Δz score were: younger age at BMD study (P<0.0001), calcium and vitamin D supplement (P<0.0001), greater dietary calcium intake (P = 0.022) and lower interval steroid dose (P = 0.005). The effect of age could be due to changes in hormonal, calcium and vitamin D metabolism or the fact that the older children might require correspondingly greater doses of calcium and vitamin D supplements. Similarly, the correlation with the interval steroid dose reinforces the contributory role of steroids in osteoporosis in these children and is also consistent with the observations in an earlier study. We did observe a greater dietary calcium intake to be a predictive of an improved Δz score, and this is consistent with the documented role of calcium in the prevention of CCS-induced bone loss. There is evidence to suggest that vitamin D plus calcium is superior to no therapy or calcium alone in the management of COP in kidney transplant patients and has been recommended as baseline therapy in patients receiving long-term CCS [7]. These have been found to be beneficial in patients with rheumatoid arthritis who were receiving long-term low-dose CCS, as well as children with cerebral palsy on antiepileptic therapy [9,18]. As CCS decrease calcium absorption from the gastrointestinal tract, supplementation with calcium and vitamin D is beneficial in preventing bone loss [9,15]. Yet, some authors have argued against the use of calcium supplements in these children [19].

Our study shows that children receiving greater steroid doses were likely to have deterioration to low BMD on follow-up. A greater dietary calcium intake as well as calcium and vitamin D supplementation were associated with reduced loss of BMD associated with CCS therapy. The most robust approach for testing this hypothesis would be a randomized control trial. However, in the light of of the data presented, we wonder whether this would be ethical. Further studies are required to optimize the dose of calcium and vitamin D supplements in these children and also to evaluate the role of bisphosphonates in the management of these children.

The authors would like to acknowledge the contributions of Mr Manoj Dubey and Mr K. K. Srivastava, technical officers in Endocrinology, who were involved in the bone density measurements of these patients. This study was funded in part by the Intramural grant programme of the Sanjay Gandhi Post Graduate Institute of Medical Sciences, India. The abstract of this paper was accepted for presentation at the XLI ERA-EDTA Congress, Lisbon, Portugal, 2004.

Conflict of interest statement. None declared.

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Author notes

1Pediatric Nephrology and 3Department of Radiology, McMaster University Medical Center, Hamilton, Ontario, Canada, 2Department of Nephrology, 4Department of Biostatistics and 5Department of Dietetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India

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