1938 Peak bone mass occurs toward the end of the third decade of life [12]. On the other hand, bone remodeling (or bone metabo- lism) is a life-long process where old bone is removed from the skeleton and new bone is added. Remodeling is initiated by damage-induced osteocyte apoptosis, which signals the location of damage via the osteocyte-canalicular system to endosteal lining cells that form the canopy of a bone remodeling compartment [7]. These processes also replace bone during growth and following injuries like fractures but also micro-damage, which occurs during normal activity. Remodeling responds to functional demands of the me- chanical loading. As a result, bone is added where needed and removed where it is not required. Molecular signaling within the bone remodeling compartment between precur- sors, mature cells, cells of the immune system, and products of the resorbed matrix titrate the birth, work, and lifespan of this remodeling machinery to either remove or form a net volume of bone. Bone modeling and remodeling processes are not very different at the cellular level. They are based on the separate actions of osteoclasts and osteoblasts. A full remodeling cycle is comprised of bone removal, or resorption, by osteoclasts followed by bone formation by osteoblasts, two processes that are tightly coupled. A schematic view of bone remodeling process is illustrated in Fig. 1. The active process of bone accumulation, or bone mass, is dependent on bone volume, height, and puberty in childhood [11]. The rate of bone remodeling is much higher in growing children [13]. In the first year of life, almost 100% of the skeleton is replaced. In adults, remodeling proceeds at about 10% per year. Both osteoclasts and osteoblasts are derived from their progenitors that reside in the bone marrow. Osteoclasto- genesis is dependent on an adequate microenvironment, which provides essential signals such as macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-κB (RANKL) and cytokines [7, 14]. Osteoblasts are cells of mesenchymal origin that are responsible for bone formation by secreting bone matrix proteins and promoting mineralization. Differentiated osteoblasts embedded in the bone matrix are termed osteocytes, and they have an important function within bone as mechanosensors and initiate bone remodeling [5]. Pre-osteoblasts express M-CSF and RANKL and can induce osteoclast formation, indicating the close interaction between bone formation and bone resorption [5, 14]. The identification of the RANKL-RANK-osteoprotegerin (OPG) system is a major breakthrough in bone biology. Disruption of the RANKL-RANK-OPG axis leads to the uncoupling of bone metabolism [2]. RANKL enhances differentiation of osteoclasts and their bone resorption capacity [15]. Several osteotropic factors, including vitamin D, parathyroid hormone (PTH) and prostaglandins promote Pediatr Nephrol (2011) 26:1937–1946 the expression of RANKL [1, 2]. The Wnt genes encode a highly conserved class of signaling factors required for the development of musculoskeletal and neural structures. Wnt signaling is critical for bone mass accrual, bone remodeling, and fracture repair [1, 16–19]. Uncoupling of the bone remodeling cycle in chronic inflammatory disorders Bone remodeling process regulates calcium homeostasis, repairs micro-damaged bones from everyday stress, and also shapes and ensures the mechanical integrity of the skeleton throughout life [3–5, 7]. An imbalance in the regulation of bone remodeling's two contrasting events, bone resorption and bone formation, results in bone loss. Chronic inflammatory diseases in children negatively influence skeletal health. Inflammation-associated bone loss can lead to growth retardation, reduced peak bone mass, and increased fracture risk [20]. Various mechanisms have been proposed for bone loss during inflammation [10]. The underlying disease process or therapeutic agents such as immunosuppressive therapies may influence bone cell function in inflammatory disorders. Chronic inflammatory diseases are often associated with cachexia [21, 22]. Cachexia is associated with anorexia and reduced nutritional intake and negatively impacts bone mass [23]. Chronic inflammation of the gastrointestinal tract reduces calorie intake and inhibits the absorption of nutrients important to bone metabolism [1]. Mildly elevated plasma homocysteine levels induced by vitamin B insuffi- ciency deteriorate normal collagen cross-link formation, an important bone quality determinant [24, 25]. Furthermore, vitamin D deficiency is often prevalent in chronic inflam- matory diseases [26]. Vitamin D deficiency reduces calcium and phosphorus absorption, increases PTH secretion, and enhances RANKL expression on osteoblasts [27]. Ele- vated expression of RANKL enhances bone resorption by promoting osteoclastogenesis. Vitamin D deficiency causes growth retardation and skeletal deformities in children [28]. In adults, vitamin D deficiency exacerbates osteopenia and osteoporosis, causes osteomalacia, and muscle weakness. Vitamin D can also modulate the immune response, and thus exerts an indirect role in inflammation-associated bone loss [29]. Physical immobility associated with chronic inflammatory conditions can lead to bone loss through reduced mechanical bone stimulation. Local or systemic inflammation causes pain, spasm, and decreased flexibility. Prolonged physical inactivity contributes to bone loss. Bone grows in response to the magnitude and direction of the forces to which it is subjected [10, 30]. This response keeps mechanically induced deformation of bone at a set point. Physical