196 The CKD-MBD is defined as a systemic disorder of mineral and bone metabolism due to CKD that is manifested by either one or a combination of the following: (1) abnormalities of calcium, phosphorus, parathyroid hormone (PTH), or vitamin D metabolism, (2) abnormal- ities in bone histology, linear growth, or strength, and (3) vascular or other soft tissue calcification. “Renal osteodys- trophy” is the specific term used to describe the bone pathology that occurs as a complication of CKD and is, therefore, one aspect of the CKD-MBD. While the definitive evaluation of renal osteodystrophy requires a bone biopsy, this procedure is not routinely performed in the clinical setting. However, bone histomorphometry continues to be the gold standard for the assessment of three essential aspects of bone histology: turnover, miner- alization, and volume [1]. Owing to new concepts and definitions of the mineral and bone alterations associated with CKD, this review outlines the current understanding of abnormal bone and mineral metabolism in CKD and current treatment strategies and their impacts on different aspects of this disorder. Abnormalities of calcium, phosphorus, PTH, and vitamin D metabolism The kidneys regulate intestinal calcium absorption by converting 25-hydroxyvitamin D3 [25(OH)D3], the storage form of vitamin D, to 1,25 dihydroxyvitamin D3 [1,25 (OH)2 D3, calcitriol], the active form of vitamin D, by means of the enzyme 1 α hydroxylase. Suppression of calcitriol synthesis occurs early in CKD, before alterations in calcium, phosphorus, or PTH levels can be detected [2, 3]. Low circulating levels of calcitriol are due, in part, to a loss of functioning renal mass and result in decreased intestinal calcium absorption, stimulating a release of PTH [4–9]. In the early stages of CKD, elevated amounts of circulating PTH may result in normal or low serum phosphate levels. In advanced stages, however, decreased glomerular filtration rate limits phosphorus excretion. Hyperphosphate- mia ensues, causing further suppression of 1 α hydroxylase activity [10] and stimulation of PTH release [11, 12]. As renal function declines, the kidneys and skeleton become increasingly resistant to the actions of PTH, necessitating higher levels of PTH to maintain normal mineral and bone metabolism [13]. While the primary stimulus for PTH is serum calcium concentration, hyper- phosphatemia also potentiates PTH secretion, while vitamin D, acting through the vitamin D receptor in parathyroid gland tissue, suppresses PTH transcription. Over time, chronic hypocalcemia, hyperphosphatemia, and Pediatr Nephrol (2008) 23:195–207 low circulating calcitriol levels result in parathyroid gland hyperplasia [14]. Since the half-life of parathyroid cells is long—on the order of 30 years—once established, hyper- plasia is difficult to reverse. PTH secretion from enlarged parathyroid glands may become uncontrollable, due to the non-suppressible basal activity of a large number of parathyroid cells. Long-term stimulation of parathyroid glands may also lead to chromosomal changes that result in autonomous, unregulated growth and hormone release [15]. A recently described phosphaturic hormone, fibroblast growth factor 23 (FGF-23), may contribute to the patho- genesis of secondary hyperparathyroidism. FGF-23 was first identified in patients with tumor-induced osteomalacia, autosomal dominant hypophosphatemic rickets, and X- linked hypophosphatemic rickets. In these conditions, elevated circulating levels of FGF-23 result in renal phosphate wasting and suppression of calcitriol production. FGF-23 levels rise as renal failure progresses, with markedly elevated levels present in individuals treated with dialysis [16]. In the early stages of CKD, increased serum FGF-23 levels are associated with suppression of calcitriol production and may thereby contribute to early stimulation of PTH release [17]. Abnormalities in bone turnover, mineralization, volume, linear growth, or strength Evaluation of skeletal histology provides both a method for understanding the pathophysiology of renal bone disease and a guide to its proper management. The routine assessment of bone histology is not performed in the clinical setting; however, current recommendations from the National Kidney Foundation [Kidney Disease Out- comes Quality Initiative (KDOQI) Guidelines] suggest that a bone biopsy should be considered in all patients with CKD who have fractures with minimal trauma (patholog- ical fractures), suspected aluminum bone disease, or persistent hypercalcemia despite having serum PTH levels between 400 pg/ml and 600 pg/ml (Level of Evidence: Opinion) [1, 18]. After double tetracycline labeling, bone tissue is obtained from the iliac crest on an outpatient basis with minimal morbidity [19, 20]. As recently recommended by the Kidney Disease Improving Global Outcomes (KDIGO) workgroup, three areas of bone histology are examined: bone turnover, mineralization and volume, all of which may be altered in patients with CKD [1]. Bone turnover Traditionally, renal osteodystrophy has been classified primarily on alterations in bone turnover. The primary