Table 1 Target PTH ranges by stage of CKD CKD stage GFR range (ml/min per 2 1.73 m ) 30–59 15–29 <15 or dialysis Target intact PTH (pg/ml) *35–70 ‡10–65 *70–110 ‡10–65 *200–300 ‡130–195 * recommended by [18], ‡ recommended by [41] Alterations in the growth hormone/insulin-like growth factor (IGF) pathway axis and their receptors also contrib- ute to growth retardation. Despite normal or elevated circulating levels of growth hormone, decreased growth hormone receptor expression results in end-organ resis- tance. Furthermore, increased levels of IGF binding proteins, in the presence of normal IGF1 levels, result in decreased bioactivity of IGF1 [42–44]. Bone deformities are also common in uremic children, due to altered skeletal remodeling. Epiphyseal widening, particularly around wrists, ankles, and the costochondral junctions (rachitic rosary), is common in infants. Slipped epiphyses, genu valgum, and femoral and wrist deformities are most common in pre-adolescent children with long- standing CKD [24, 45]. Avascular necrosis of the femoral head and pathologic fractures of the extremities and chest wall due to osteoporosis and bone deformities may occur with minimal trauma. In addition, vertebral crush fractures contribute to significant morbidity in this population. The initial management of skeletal deformities requires the normalization of serum calcium, phosphorus, and PTH levels. Surgical correction is often also necessary but should be performed only after correction of biochemical abnormalities [18]. Biomarkers of renal osteodystrophy Serum calcium and phosphorus Serum calcium and phosphorus levels remain stable in mild-to-moderate stages of CKD. As renal failure advances, however, serum calcium levels drop in response to decreased intestinal calcium absorption resulting from low circulating levels of 1,25(OH)2D3 [2]. Treatment with active vitamin D sterols and phosphate binders corrects hypocalce- mia, and, in stage 5 CKD, hypercalcemia may develop in response to aggressive treatment with high doses of vitamin D sterols and calcium-based phosphate binders. In this context, increased serum calcium, in conjunction with low levels of 198 3 4 5 Pediatr Nephrol (2008) 23:195–207 PTH and alkaline phosphatase, may signal the development of adynamic bone [32]. Adjustment of vitamin D dosage and the use of non-calcium-containing phosphate binders can prevent the development of this complication as well as its associated growth failure [32]. Avoidance of increased serum calcium levels, which are associated with an increased risk of mortality in large populations of adult dialysis patients, also may prevent the progression of cardiovascular calcification (vide infra) [46, 47]. Similar to those of serum calcium, serum phosphorus levels remain within the normal range until CKD stages 4 to 5 are reached, when decreased GFR limits urinary phosphate excretion. Serum PTH levels rise but fail to compensate for phosphorus retention [2]. In stage 5 CKD, traditional hemodialysis or peritoneal dialysis typically removes less than half of ingested phosphate, necessitating the use of phosphate binders to control serum phosphorus and PTH levels. Since elevated values for the serum calcium × phosphorus product have been associated with vascular calcification and increased rates of mortality [48– 50], maintaining serum calcium and phosphorus levels within the normal range is important for optimizing cardio- vascular health in all stages of CKD (vide infra) [18]. Alkaline phosphatase activity Serum alkaline phosphatase values are fair markers of osteoblastic activity in children with CKD. Osteoblasts normally express large amounts of the bone isoenzyme of alkaline phosphatase, and elevated serum levels correlate with increased bone formation, high levels of serum PTH, and growth hormone therapy [51]. Since alkaline phospha- tase is also present in the liver, elevated serum levels of total alkaline phosphatase may not always indicate in- creased bone turnover. Measurement of the heat-stabile and heat-labile fractions may help to separate skeletal from hepatic causes of elevated levels. Alkaline phosphatase measurements are useful in monitoring the skeletal re- sponse to treatment with vitamin D sterols in patients with osteitis fibrosa; values that decrease over several months usually indicate histologic improvement [52]. However, consistently low serum alkaline phosphatase values, partic- ularly in children with stage 5 CKD receiving large doses of vitamin D sterols and calcium-containing phosphate binders, are consistent with adynamic bone [32]. Parathyroid hormone Serum PTH levels are widely used as non-invasive markers in distinguishing low-turnover lesions from osteitis fibrosa [33, 53]. Current recommendations for target PTH levels are based on measurements obtained by the 1st generation PTH assay in cross-sectional bone biopsy data from children