Prevention and Treatment of Bone Disease in Pediatric Dialysis Patients

Childhood and adolescence are crucial times for developing a healthy skeletal system; alterations in bone modeling/remodeling in youth carry consequences that severely impact quality of life even into adulthood. In childhood, chronic kidney disease (CKD) causes disordered regulation of mineral metabolism, with subsequent alterations in bone modeling, remodeling, and growth. Additionally, uremia itself, independent of altered mineral metabolism, impairs bone cell function in a manner that contributes to bone disease. CKD-mediated alterations in bone structure, strength, and growth are termed “renal osteodystrophy” (ROD). Due to the link between bone disease, abnormal mineral metabolism, and cardiovascular disease in uremic patients, ROD is one part of the systemic disorder that is termed the “CKD–mineral and bone disorder” (CKD-MBD).

This chapter first describes the clinical manifestations of ROD. Pathologic changes at the level of bone are also described. The pathogenesis of secondary hyperparathyroidism and the effects of uremia on bone cell biology are discussed, followed by the biomarkers of bone disease and current treatments for secondary hyperparathyroidism and ROD.

Clinical Features of Renal Osteodystrophy

Growth Failure

Growth retardation is the hallmark of CKD in children. Growth failure is present in children with even mild CKD and worsens as renal function declines. Despite optimal control of bone disease and the availability of recombinant human growth hormone (rhGH), the average height of children starting dialysis is 1.5 standard deviation scores below normal. Growth worsens in dialysis patients, and by transplantation, height is 1.7 SD below that in healthy children. Boys, younger patients, and those with prior renal transplants are at greatest risk for growth failure. Acidosis, anemia, calcitriol deficiency, secondary hyperparathyroidism, and bone deformities all contribute to growth retardation. Overtreatment of secondary hyperparathyroidism with large, intermittent doses of calcitriol and calcium-based phosphate binders may cause adynamic bone disease, which is associated with decreased linear bone growth, despite sometimes elevated serum parathyroid hormone (PTH) levels. Resistance to the actions of growth hormone (GH) also contributes to impaired linear growth in renal failure. Growth velocity increases during rhGH therapy as bioavailability of insulin-like growth factor 1 (IGF1) increases to target tissues.

Due to a variety of factors, a significant proportion of dialyzed children who are candidates for GH therapy do not receive it. Although children who are treated with maintenance dialysis respond less well to rhGH therapy than do children with less severe CKD, this resistance should not prevent these children from receiving rhGH. Current recommendations suggest that children on dialysis who have growth potential should receive rhGH if they have persistent growth failure, defined as a height below the third percentile for age and sex and a height velocity below the 25th percentile, once other potentially treatable risk factors for growth failure have been adequately addressed.

Deformities and Bone Fragility

Decreased bone strength is a clinical feature of CKD-MBD that afflicts children even in early CKD stages. In a prospective cohort of children with CKD, fracture rates were 2 to 3 times those observed in the general population. Advanced pubertal stage, taller height, and higher PTH levels were associated with increased fracture risk, suggesting that the combination of high turnover osteodystrophy and pubertal growth increases bone fragility in the pediatric CKD population; interestingly, the use of phosphate binders (mainly calcium based) was protective. However, it is also important to note that as many as 20% of this population had mild (stages 1 and 2) CKD, suggesting that bone fragility contributes to morbidity in children at all CKD stages. Bone deformities are also common. Genu valgum is the most common skeletal deformity in pubescent and adolescent CKD patients, while young children may exhibit exaggeration of the physiologic varus alignment. Radiographic features associated with rickets, such as metaphyseal widening of the wrist and ankle, craniotabes, and rachitic rosary, may occur. Pathologic or stress fractures may arise if the bones remain bowed and weak.

Pathology of Renal Osteodystrophy: Abnormalities in Bone Turnover, Mineralization, and Volume

Renal bone disease (ROD) is nearly universal in children starting dialysis. Traditionally, ROD has been defined by changes in trabecular bone turnover, ranging from high bone turnover (osteitis fibrosa) to lesions of low bone turnover (adynamic bone disease and osteomalacia). However, alterations in skeletal mineralization and volume are also common in pediatric dialysis patients and may contribute to outcomes such as fractures, skeletal deformities, and poor growth, which persist despite normalization of bone turnover. Even though it is rarely available in daily clinical practice, bone histomorphometry remains the gold standard for the diagnosis of ROD.

Turnover

Abnormalities in bone turnover—both excessively low and excessively high—are prevalent in pediatric CKD patients. High bone turnover is the most common lesion in children treated with maintenance dialysis. Excessive PTH concentrations result in increased bone matrix resorption with concomitant release of minerals into the circulation. Prolonged exposure to elevated PTH levels and increased bone turnover may lead to fibrous changes in bones; thus, the ROD associated with prolonged secondary hyperparathyroidism is often termed “osteitis fibrosa cystica.”

A state of low-turnover bone disease (adynamic ROD), defined as decreased bone formation rate in conjunction with decreased cellular activity and an absence of excessive osteoid accumulation, is most common in adult dialysis patients but may also occur in children treated with overaggressive active vitamin D sterols and calcium salt therapy. In addition to the increased risk that is also observed in adults with low bone turnover, adynamic bone disease in children treated with dialysis is associated with exacerbated growth failure.

Mineralization

Alterations in skeletal mineralization, defined by increased accumulation of unmineralized bone (osteoid) in conjunction with delayed rates of mineral deposition, are prevalent in children with CKD. Defective mineralization that is associated with low to normal bone turnover is termed “rickets” in growing children, and its histomorphometric characteristics include wide osteoid seams, increased numbers of osteoid lamellae, increased percentage of trabecular surface covered with osteoid, and a diminished rate of mineralization or bone formation, as assessed by double tetracycline labeling. Fibrosis is typically absent. Defective mineralization in combination with increased bone formation rates is termed “mixed uremic osteodystrophy” and is characterized by wide osteoid seams, prolonged mineralization times, bone marrow fibrosis, and increased bone formation rates.

Volume

Because PTH is anabolic at the level of trabecular bone, high levels of serum PTH are typically associated with increases in bone volume, trabecular volume, and trabecular width. Low bone volume is rare in the pediatric CKD population.

Circulating Factors Contributing to Renal Osteodystrophy

With the exception of a few well-defined monogenetic disorders, such as cystinosis, oxalosis, and autosomal dominant polycystic kidney disease, which have direct deleterious effects on the skeleton, the pathologic features of ROD are remarkably similar in children with end-stage kidney disease (ESKD) regardless of the underlying disease. This suggests that the uremic milieu itself, rather than underlying genetics, contributes to the majority of the ROD phenotype in this population.

While not all the factors contributing to bone disease in this population are known, disturbance in mineral ion homeostasis has been well characterized. More recent data suggest that uremic toxins themselves also influence bone cell biology, contributing to important features of bone disease.

Calcium and Phosphorus

Since childhood and adolescence are critical times for developing a healthy skeleton, with the skeletal calcium content increasing from 25 g at birth to 1000 g in adulthood, hypocalcemia directly results in decreased volumetric bone mineral density (BMD) scores in growing children. By contrast, hypercalcemia oversuppresses PTH secretion, thus, leading to low bone turnover (adynamic bone disease). While hyperphosphatemia drives secondary hyperparathyroidism (as earlier), phosphate depletion may play a major role in the development of rickets/osteomalacia in patients treated with frequent (daily) dialysis and/or with inadequate nutrition.

Acidosis

Not only is chronic acidosis is a risk factor for more rapid CKD progression in children, but also, it is associated with poor skeletal mineralization as free hydrogen ions directly release calcium from bone. In addition, acidemia stimulates osteoclast differentiation and osteoclast-mediated bone resorption and inhibits osteoblastic-driven mineralization. Thus untreated acidosis likely contributes to the high prevalence of skeletal mineralization observed in dialyzed children.

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