1940 resulting in negative bone balance. Pro-inflammatory cytokines such as IL-6 and IL-1β promote the expression of calcium-sensing receptor and result in decreased circu- lating PTH and vitamin D levels [35, 36]. Anti-TNF-α therapy is very effective in treating patients with inflam- matory disorders. This treatment improves the underlying condition but also appears to have an independent benefi- cial effect on bone, probably via the inhibition of osteoclastogenesis [1]. An additional mechanism by which inflammation uncouples bone remodeling cycle is through alternation of glucocorticoid signaling [1]. Glucocorticoids suppress inflammation and help to resolve underlying illness. However, glucocorticoid treatment has been associated with osteopenia in chronic inflammatory disease [37]. Glucocorticoids reduce osteoblast protein synthesis [38]. While glucocorticoids at physiological doses are essential for normal osteoblast differentiation [39], glucocorticoids at high doses diminish the number of osteoblasts by promot- ing apoptosis [40]. Glucocorticoids can also cause muscle wasting [41]. Glucocorticoid-induced myopathy may con- tribute to bone deficits via the functional muscle-bone unit. Recent studies suggest divergent effects of glucocorticoids on bone metabolism. There is currently debate in the pediatric bone field regarding the skeletal effects of glucocorticoids. Results suggested that children with oral corticosteroid treatment were at a greater risk of bone fracture, likely due to decreased bone formation [37]. Modest deficits in bone mineral content (BMC) in the lumbar spine but greater whole body BMC and femoral shaft dimensions were observed in pediatric patients with steroid-sensitive nephrotic syndrome compared with con- trols [42]. In a follow-up study, glucocorticoids in child- hood nephrotic syndrome were associated with low trabecular bone mineral density (BMD) but high cortical BMD and increased cortical dimensions were related to increased muscle mass [43]. Bone mass regulation in rheumatic diseases Rheumatoid arthritis, juvenile idiopathic arthritis, the seronegative spondyloarthropathies including psoriatic ar- thritis, and systemic lupus erythematosus are all examples of rheumatic diseases in which inflammation is associated with skeletal pathology [44]. Although some of the mechanisms of skeletal remodeling are shared among these diseases, each disease has a unique impact on articular bone or on the axial or appendicular skeleton [45, 46]. Studies in human disease and in animal models of arthritis have identified the osteoclast as the predominant cell type mediating bone loss in arthritis [44, 47]. Many of the cytokines and growth factors implicated in rheumatic Pediatr Nephrol (2011) 26:1937–1946 diseases have been demonstrated to impact osteoclast differentiation and function either directly, by acting on cells of the osteoclast-lineage, or indirectly, by acting on other cell types to modulate expression of the key molecules such as RANKL and its inhibitor OPG [48]. Reduced BMD and bone strength occurs in pediatric patients with rheumatoid arthritis [20, 49]. The hallmark of rheumatoid arthritis is inflammation of the synovium. The synovium becomes hyperplastic and inflamed, which is driven by innate and adaptive immune responses and subsequently invades the articular cartilage, causing bone erosions [50, 51]. Bone loss in the inflamed joint is also due to the uncoupling of bone remodeling. Pro- inflammatory cytokines released by activated immune cells in the inflamed joints promote osteoclast activity and bone erosion [1, 2, 51]. IL-17 recruits neutrophils to the inflamed joint and activates osteoclast differentiation by increasing the expression of RANK/RANKL in synoviocytes [52]. IL-17 also decreases the expression of OPG in osteoblastic cells, which promotes osteoclasto- genesis and induces local bone erosion [53]. Other pivotal pro-inflammatory cytokines present in the arthritic joint include TNF-α, IL-6, IL-1, and IL-10 [54]. An additional pathway in which rheumatoid arthritis affects bone mass is through paracrine activity of 11β-hydroxysteroid dehydro- genases (11β-HSDs), potentially a major mechanism by which osteoblasts and osteoclasts are uncoupled [1]. Activ- ities of 11β-HSDs were stimulated by pro-inflammatory cytokines, specifically IL-1 and TNF-α, suggesting that these factors might contribute to inflammation-mediated bone loss [55–58]. Juvenile idiopathic arthritis is the most common pediat- ric rheumatic disease [59] and affects joints in any part of the body. In this disease, the synovium and inflammation process can spread to surrounding tissues, eventually damaging cartilage and bone. Other areas of the body, especially the eyes, may also be affected by the inflamma- tion. Without treatment, juvenile idiopathic arthritis can interfere with a child’s normal growth and development. Burnham et al. have evaluated the bone density, structure, and strength in 101 pediatrics patients with juvenile idiopathic arthritis as compared to 830 healthy control subjects. Significant reduction in trabecular volumetric BMD and reduced bone strength was observed among those patients [20, 49, 60, 61]. Children with juvenile idiopathic arthritis are at risk for deleterious alternations in cortical bone strength and trabecular bone density, placing them at greater risk of bone fracture. The pronounced bone deficits are greater than would be expected for their reductions in muscle cross-sectional area. Thus, bone alternations in juvenile idiopathic arthritis could represent a mixed defect of bone development and low muscle forces [49].