Pediatr Nephrol (2011) 26:1937–1946 Bone mass regulation in inflammatory bowel disease Low BMD is common in patients with inflammatory bowel disease [62, 63]. Poor nutrition, physical inactivity, expo- sure to glucocorticoids, decreased muscle mass, inflamma- tory cells, and cytokines all contribute to low BMD in inflammatory bowel disease. Nutritional supplementations have reversed growth impairment in patients with inflam- matory bowel disorder and benefited bone mineralization [51]. Lean tissue mass correlated positively with lumbar spine and total body BMD. Increased lean tissue mass may be related to improved physical activity which in turn, may increase BMD in children with inflammatory bowel disease [51, 64–67]. Vitamin D deficiency may play a role in the pathological process of bone loss in inflammatory bowel disease. Low serum 25-hydroxyvitamin D levels have been reported in patients with chronic inflammatory bowel disease [68]. Soluble factors released by the inflamed intestine may impair bone formation [69]. Activated lymphocytes are present in the inflamed intestinal mucosa in inflammatory bowel disease. Activated lymphocytes and their secreted cytokines affect bone cell function. TNF-α and IFN-γ inhibit osteoblast formation and function, and TNF-α stimulates osteoclast formation via RANKL. Neu- tralization of TNF-α in patients with inflammatory bowel disease is associated with a rise in bone formation biomarkers and improved BMD [65, 70]. Sylvester et al. reported inconsistent findings with regard to biomarkers of bone resorption in pediatric patients with Crohn’s disease. Urinary N-telopeptides of collagen levels were decreased while urine deoxypyridinoline to creatinine ratios were not [71]. Possible reasons for the lack of elevated resorption markers in Crohn’s disease in the Sylvester’s study may be contributed to study design and analytic approach. Recent studies suggest that biomarkers of bone metabolism vary significantly with many con- founding factors such as age, sex, and Tanner stage with a peak during the pubertal growth spurt followed by a rapid decline to adult levels [72–76]. After adjustment for these effects, Tuchman et al. reported that Crohn’s disease was associated with lower biomarkers of bone formation and greater bone resorption [66]. Beneficial anti-inflammatory effects of glucocorticoids may offset some of its negative effects on bone. Dubner et al. carried out an elegant study in children with new-onset of Crohn’s disease. Their protocol was rigorously designed to adjust for numerous variables that may affect bone density, structure, or strength in the participants. In this study, glucocorticoid treatment was directly correlated with increased cortical BMD Z-score after 6 months, and the absence thereof with declines in cortical BMD in the subsequent 6 months [64]. The authors speculated that glucocorticoids may lead to a reduction in bone turnover, possibly causing reduced 1941 intracortical porosity, greater secondary mineralization, and higher cortical BMD. 11β-HSD1 is induced by inflammatory cytokines [1, 77]. Upregulation of 11β-HSD1 is documented in colonic mucosa in experimental colitis [78] and in patients with inflammatory bowel disease [79]. Un-regulation of 11β-HSD1 increases the sensitivity of the colon to thera- peutic glucocorticoids [1, 80]. A high 11β-HSD1 activity in the inflamed colon may lead to more effective anti- inflammatory effects on the colon, enabling a lower level of glucocorticoids to be used. This could have a potential bone-sparing effect. Bone mass regulation in chronic kidney disease Reductions in BMD are common in patients with chronic kidney disease (CKD) and may increase susceptibility to low- trauma fracture [81, 82]. Multiple factors may attribute to decreased bone formation in chronic kidney disease (Fig. 2). A wide spectrum of skeletal manifestations may occur in CKD [83]. Renal osteodystrophy is important in CKD children because of the risk of long-term consequences such as growth retardation and bone deformalities [84, 85]. Growth failure is a significant problem in CKD [86]. Pediatric patients have unique problems because CKD profoundly interferes with bone growth and mineralization [87, 88]. Secondary hyperparathyroidism is associated with excessive bone resorption and high turnover bone disease whereas sub-optimal PTH levels may cause low turnover bone disease [89]. Recent findings suggest that inflammation negatively impacts bone mass in CKD. IL-6, the major mediator of the acute-phase inflammation, is elevated in CKD patients [90]. A number of factors such as hyperten- sion, adiposity, insulin resistance, fluid overload, persistent infections, genetic variations of IL-6 gene, reduced renal function, and dialysis per se have been implicated in the pathogenesis of increased IL-6 levels in CKD [91, 92]. Increased circulatory levels of IL-6 may uncouple bone remodeling in end-stage renal disease (ESRD). IL-6 affects bone turnover independently of PTH. An inverse correlation between serum IL-6 and the bone turnover markers osteocalcin and β-isomerized C-terminal cross-linked pep- tide of collagen type I was documented in hemodialysis patients [93]. Indeed, calcitriol treatment affects bone remodeling by influencing the levels of plasma IL-6, beyond its suppressive effect on PTH [94]. IL-6, synthesized by osteoblasts in response to PTH, stimulates osteoclastogenesis and bone resorption in vitro, and has been implicated in the pathogenesis of bone loss in several inflammatory con- ditions. Increased serum IL-6 levels were associated with elevated bone resorption rate in uremic patients with renal osteodystrophy [95]. IL-6, released from human osteoblastic cells in the uremic milieu, has been implicated in the