Glucocorticoid effects on changes in bone mineral density and cortical structure in childhood nephrotic syndrome

Abstract

The impact of glucocorticoids (GC) on skeletal development has not been established. The objective of this study was to examine changes in volumetric BMD (vBMD) and cortical structure over one year in childhood nephrotic syndrome (NS) and to identify associations with concurrent GC exposure and growth. Fifty-six NS participants, ages 5–21 years, were enrolled a median of 4.3 (0.5, 8.1) years after diagnosis. Tibia peripheral quantitative CT (pQCT) scans were obtained at enrollment and 6 and 12 months later. Sex, race and age-specific Z-scores were generated for trabecular vBMD (TrabBMD-Z), cortical vBMD (CortBMD-Z), and cortical area (CortArea-Z) based on > 650 reference participants. CortArea-Z was further adjusted for tibia length-for-age Z-score. Quasi-least squares regression was used to identify determinants of changes in pQCT Z-scores. At enrollment, mean TrabBMD-Z (−0.54 ±1.32) was significantly lower (p=0.0001) and CortBMD-Z (0.73 ± 1.16, p<0.0001) and CortArea-Z (0.27 ± 0.91, p=0.03) significantly greater in NS, vs. reference participants, as previously described. Forty-eight (86%) participants were treated with GC over the study interval (median dose 0.29 mg/kg/day). On average, TrabBMD-Z and CortBMD-Z did not change significantly over the study interval; however, CortArea-Z decreased (p=0.003). Greater GC dose (p<0.001), lesser increases in tibia length (p<0.001) and lesser increases in CortArea-Z (p=0.003) were independently associated with greater increases in CortBMD-Z. Greater increases in tibia length were associated with greater declines in CortArea-Z (p < 0.01); this association was absent in reference participants (interaction p<0.02). In conclusion, GC therapy was associated with increases in CortBMD-Z, potentially related to suppressed bone formation and greater secondary mineralization. Conversely, greater growth and expansion of CortArea-Z (i.e. new bone formation) were associated with declines in CortBMD-Z. Greater linear growth was associated with impaired expansion of cortical area in NS. Studies are needed to determine the fracture implications of these findings.

Skeletal findings in the first 12 months following initiation of glucocorticoid therapy for pediatric nephrotic syndrome

“…This is important, since DXA does not differentiate between these two structures, yet studies have shown divergent effects of GC on the two compartments [41]. Tsampalieros et al [42] recently studied a longitudinal cohort of pediatric NS treated with a similar initial GC regime as in our study, and found that tibia trabecular volumetric BMD Z-scores were lower and cortical density and area Z-scores higher compared to controls around the time of diagnosis. Over the one-year follow-up period, trabecular and cortical BMD Z-scores did not change significantly; however, there was a decrease in cortical area Z-score that was hypothesized to result from a dampening effect of GC therapy on cortical modeling (i.e.…”

“…Given the high cortical density and low trabecular Z-scores observed at diagnosis and after 12 months of GC therapy in the study by Tsampelieros et al [42], when these two compartments are combined in the anterior-posterior DXA measurement, any net changes in the sum of the compartments must be considered in view of the more limited DXA technique. As such, longitudinal observations that show increases in BMD Z-scores by DXA over time (such as in our report) need to consider that such increases could arise from an increase in cortical density (which may not be beneficial to bone strength), or improvement in previously low trabecular density.…”

Skeletal outcomes by peripheral quantitative computed tomography and dual-energy X-ray absorptiometry in adolescent girls with anorexia nervosa

“…If AN induces suppression of cortical modeling, older bone with greater material density will accumulate, leading to greater cortical vBMD. This effect has been previously described in cohorts of children and adolescents receiving chronic glucocorticoid therapy for renal disease [17, 32]. Long-term glucocorticoid therapy led to reduced bone formation markers, decreased height Z-scores, and elevated cortical vBMD Z-scores [32].…”

“…This effect has been previously described in cohorts of children and adolescents receiving chronic glucocorticoid therapy for renal disease [17, 32]. Long-term glucocorticoid therapy led to reduced bone formation markers, decreased height Z-scores, and elevated cortical vBMD Z-scores [32]. This finding is of concern, since too much bone mineralization can lead to brittle bones [33] and thus to increased fracture risk [34, 35].…”

A biomechanical sorting of clinical risk factors affecting osteoporotic hip fracture

“…Significant decrease in bone mineral density has been found in chronic users of glucocorticoids [186][187][188][189]. Even high levels of natural glucocorticoids in the body are also associated with reduced bone-forming and increased bone breakdown [190].…”