Bone histology in steroid-treated children with non-azotemic nephrotic syndrome

Abstract

Patients with nephrotic syndrome (NS) and normal glomerular filtration rate (GFR) frequently exhibit abnormalities of calcium and vitamin D homeostasis, mainly hypocalcemia and reduced circulating vitamin D metabolites. These abnormalities have been linked to alterations of bone histology in adults with non-azotemic NS, particularly osteomalacia and excessive bone resorption. Whether similar abnormalities of bone histology occur in children and adolescents with NS, particularly in those requiring prolonged treatment with corticosteroids, remains largely unknown. Thus, bone histomorphometry and selected bone-modulating hormones were studied in eight children (aged 2-16 years) with normal GFR (range 85-169 ml/min per 1.73 m(2)) and NS. All patients received corticosteroids for at least 12 months prior to bone biopsy. At the time of bone biopsy, the urine protein/creatinine ratio was elevated (2.1+/-3.6), while the average concentrations of parathyroid hormone (36+/-13 pg/ml), 25-hydroxyvitamin D [25(OH) D] (22+/-14 ng/ml), and 1,25(OH)(2)D (59+/-22 pg/ml) were normal. Bone histomorphometry displayed focal osteomalacia (OM) and mild increased bone resorption in most patients. The mineralization lag time, an indicator of the degree of osteomalacia, correlated with the time elapsed since the original diagnosis of NS ( r=0.93, P<0.0005). Overt hyperparathyroidism was not evident, but increased eroded perimeter and elevated bone formation rate (BFR) were evident in two patients, suggesting high-turnover bone disease. The BFR was inversely correlated with the administered dose of prednisone at the time of biopsy ( r=-0.78, P<0.05) and one patient exhibited low bone turnover changes. The growth velocity standard deviation score (SDS) at time of biopsy ranged from -1.6 to 3.2, resulting in a height SDS range of -1.9 to 0.6. The height SDS at time of bone biopsy correlated inversely with the dose of administered glucocorticoid ( r=-0.71, P<0.05) and with the duration of the disease ( r=-0.7, P=0.05). These data, albeit preliminary, demonstrate that children with NS treated with prolonged corticosteroid therapy exhibit bone histopathological changes without a concomitant impairment in GFR. While the OM appears to be related to the disease process, the alterations of bone formation and the adynamic changes are likely the result of the corticosteroid therapy. The potential consequences of these findings on adult bone mass and ultimate height deserve further studies.

Vitamin D in incident nephrotic syndrome: a Midwest Pediatric Nephrology Consortium study

“…When appropriate corrections for body size are employed, the literature has been consistent on documenting a negative impact of steroid exposure on bone health in children with NS [21, 22]. Studies utilizing bone biopsy data have demonstrated abnormalities in the bones of children with NS treated with steroids, including increased focal osteomalacia and bone resorption relative to controls [30]. Recently, Choudhary et al performed an interventional trial in children with new-onset NS, which showed that children with incident disease had abnormalities in bone mineral content at 12 weeks, and supplemental calcium and vitamin D were protective against these bone abnormalities [24].…”

Bone histomorphometric changes in children with rheumatic disorders on chronic glucocorticoids

“…Adults with rheumatoid arthritis have been shown to have evidence of decreased trabecular bone volume and turnover [15, 35]. Reduced trabecular thickness and osteoblast surface have similarly been found in other cohorts of children treated with glucocorticoids such as those with Duchene muscular dystrophy and steroid dependent nephrotic syndrome [21, 22]. Unlike, however, the histomorphometry results from the pediatric patients with nephrotic syndrome, our subjects did not have evidence of osteomalacia, as seen by the reduced osteoid thickness and volume.…”

“…Studies of bone histomorphometry and mineralization in pediatric patients treated with glucocorticoids have contributed to the understanding of underlying pathology and clinical factors with the potential to predict severity of bone disease [21, 22]. Given these features have not to date been described in pediatric rheumatalogical patients, the aims of this pilot study were therefore to characterize bone histomorphometry and mineralization in a small cohort of children with rheumatic diseases and to assess associations between clinical and radiological indices to bone micro-architecture.…”