KDOQI (Kidney Disease Outcomes Quality Initiative)


NKF KDOQI GUIDELINES

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KDOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Children With Chronic Kidney Disease


Guideline 14. Treatment of Bone Disease in CKD

The treatment of bone disease in CKD is based on its specific type. This Guideline encompasses three parts: Guideline 14A deals with high-turnover bone disease; Guideline 14B with rickets/osteomalacia; and Guideline 14C with adynamic bone disease.

Guideline 14A. Hyperparathyroid (High-Turnover) Bone Disease

14A.1 In CKD patients who have serum PTH levels >70 pg/mL (Stages 2-3) or >110 pg/mL (Stage 4), dietary phosphate intake should be modified according to Guidelines 5 and 6, and dietary calcium should be modified according to Guideline 7. Nutritional vitamin D insufficiency or deficiency should be corrected according to Guideline 8. If a repeat 1st PTH-IMA after 3 months of dietary intervention shows that PTH levels remain elevated, then patients should be treated with calcitriol or 1-α-vitamin D2 (EVIDENCE), to prevent or ameliorate high-turnover bone disease.

14A.2 In CKD Stage 5 patients who have elevated serum PTH levels >300 pg/mL despite modification of dietary phosphate intake according to Guidelines 5 and 6, calcitriol or 1-α-vitamin D2 (EVIDENCE) should be used to reverse the bone features of hyperparathyroidism (i.e., high-turnover bone disease).

Background

In the untreated patient, studies in adults and children with CKD Stage 5 have shown that high-turnover bone disease is often associated with serum levels of PTH >300 pg/mL. High-turnover bone disease may also be seen at similar PTH values despite treatment with daily low-dose calcitriol or intermittent high-dose calcitriol therapy in CKD Stage 5.

Rationale

The understanding of bone disease in CKD has evolved dramatically over the years. The recognition that hyperparathyroidism is a complication of kidney failure may predate by many years the initiation of dialysis treatment. Early studies of osteodystrophy focused largely on understanding the pathophysiology and the prevention of severe hyperparathyroid bone disease. The development of more specific 1st PTH-IMA facilitated more accurate classification of the different forms of renal osteodystrophy.

Limitations

See the corresponding section in Guidelines 8 and 9. There are no published data on the correlation between PTH levels and bone histology in children with CKD Stages 2-4. At this time, there are no data to support the use of bisphosphonates in children with renal osteodystrophy (see Guideline 16).

Recommendations for Research

Studies are needed to evaluate the changes in bone histology, iPTH, and PTH fragments with the available vitamin D analogs and other therapeutic approaches for the treatment of renal osteodystrophy. The relationship among iPTH, PTH fragments, vitamin D therapies, and linear growth needs to be established in children with CKD. The influence of GH in osteodystrophy is incompletely known at this time and needs further study. Randomized clinical trials should be conducted in order to determine the effects of vitamin D therapies on bone histology and growth in children on maintenance dialysis.

Guideline 14B. Rickets/Osteomalacia

14B.1 Rickets and osteomalacia due to aluminum toxicity should be prevented in dialysis patients by maintaining aluminum concentration in dialysate fluid at <10 µg/L and by avoiding the use of aluminum-containing compounds. (OPINION)

14B.2 Rickets and osteomalacia due to vitamin D deficiency should be treated according to Guideline 7. (EVIDENCE)

14B.3 Rickets and osteomalacia due to hypophosphatemia should be treated with neutral sodium phosphate salts. Concomitant active vitamin D therapy should be considered. See Guidelines 7 and 8. (EVIDENCE)

Background

As aluminum accumulates on bone surfaces, it impairs bone formation, leading to either rickets, osteomalacia, or adynamic bone disease. Since this was recognized and aluminum exposure curtailed, osteomalacia has largely disappeared. However, patients may still be seen with this problem and its diagnosis and treatment need to be understood. If osteomalacia is found in the absence of aluminum, it is often related to pre-existing tubular defects of phosphate depletion, or vitamin D2 or D3 deficiency. While the incidence of aluminum bone disease has been greatly reduced it still may occur and its diagnosis and treatment should be addressed. Osteomalacia may occur in the absence of aluminum exposure and is often related to hypophosphatemia or vitamin D deficiency.

Rationale

In the late 1970s, it was documented that rickets or osteomalacia occurred in patients with CKD secondary to aluminum intoxication. The clinical manifestations in children include bone pain, bone deformities, deranged mineral ion homeostasis, and reduced linear growth. In children, aluminum toxicity may cause neurological manifestations, including seizures, microcephaly, development delays, and encephalopathy. When marked aluminum loading occurs, brain abnormalities develop which, if untreated, are usually lethal. Treatment with a chelating agent, such as DFO, may improve patients' bone disease and neurological abnormalities in children with CKD. Rickets and osteomalacia occur in children with CKD in the absence of aluminum intoxication. The avoidance of aluminum has largely eliminated aluminum-related osteomalacia as a clinical problem in the dialysis population. Occasionally, dialysis patients may present with osteomalacia not associated with aluminum intoxication. This may be due to vitamin D deficiency, hypophosphatemia or metabolic acidosis, drugs (inducers of cytochrome P450 pathways), alcohol, calcium and/or phosphate deficiency, or other toxins.

Strength of Evidence

There is compelling evidence of the role of aluminum in the development of rickets and osteomalacia. For detailed discussion, see the corresponding sections in Guidelines 11 and 12.

Limitations

Due to the severe clinical outcome of osteomalacia and other complications resulting from aluminum toxicity, no placebo-controlled studies of its treatment are possible.

Clinical Application

A DFO challenge test (see Guidelines 12 and 13) can often identify aluminum overload, but is not specific for the presence of bone lesions. The diagnosis of bone aluminum accumulation and its associated histological derangements requires a bone biopsy (see Guideline 12). Treatment approaches to nonaluminum-related osteomalacia need to be tailored according to the underlying mechanism. Treatment should be continued until clinical laboratory indicators of osteomalacia and the associated metabolic acidosis have disappeared.

Recommendations for Research

Aluminum accumulation in bone has become much less frequent as the use of aluminum-containing phosphate binders has declined. Unfortunately, the calcium-based binders which have largely replaced aluminum-containing phosphate binders may be associated with calcium overload, hypercalcemia, and vascular calcification. Studies need to evaluate the safety and efficacy of non-metal-containing phosphate binders.

Guideline 14C. Adynamic Bone Disease

14C.1 In CKD Stage 5, adynamic bone disease not related to aluminum (as determined either by bone biopsy or suggested by PTH <150 pg/mL) should be treated by allowing serum levels of PTH to rise in order to increase bone turnover. (OPINION)

14C.1.a The increase in PTH levels can be accomplished by discontinuing treatment with activated vitamin D analogs, decreasing or eliminating the use of calcium-based phosphate binders, reducing the dialysate calcium concentration (see Guideline 8) (EVIDENCE), and/or using a metal-free phosphate binder. (OPINION)

Background

The prevalence of adynamic bone disease has increased with more frequent use of vitamin D analogs and calcium-based phosphate binders. Adynamic bone disease has been reported in children and adolescents receiving hemodialysis or peritoneal dialysis. The clinical sequelae of adynamic bone disease are the risk of bone fractures, impairment of linear growth, and the inability of adynamic bone to contribute to overall mineral ion homeostasis.

Rationale

With the use of high-dose calcium salts for phosphate binding, and more frequent and aggressive vitamin D treatment, adynamic bone lesions have become increasingly common as demonstrated by bone histomorphometric studies.514  The disease has been ascribed to insufficient levels of PTH (<150 pg/mL in patients with CKD Stage 5) due to the use of active vitamin D analogs, chronic positive calcium in excess of that needed for growth, or following subtotal parathyroidectomy.22,327,515

Although blood levels of PTH (<150 pg/mL) strongly suggest the presence of adynamic bone disease, adynamic bone disease may occur at higher levels of PTH often associated with hypercalcemia or hyperphosphatemia. Bone biopsy may therefore be required to establish or rule out the diagnosis of adynamic bone disease. Accumulating data in adults with CKD Stage 5 suggest that evidence for adynamic bone disease by histology is not benign. In this dialysis population, there is a four-fold increase in hip fracture risk compared to the general population.516,517 Age, duration of dialysis, female sex, and diabetes appear to confer an increased risk for fracture in such patients. In children with CKD Stage 5, the clinical manifestations of adynamic bone disease are not well characterized. The single study in children that included bone histomorphology demonstrated that adynamic bone disease in the setting of high-dose calcitriol therapy was associated with impaired linear growth.518 The relatively inert, adynamic bone does not allow an appropriate deposition of calcium into bone and thus leads to impaired regulation of blood calcium. Because of the inability to deposit calcium into bone, calcium loading (for example, by oral calcium-containing phosphate binders or by loading through dialysate calcium) often leads to marked hypercalcemia. In addition, with the failure of the bone to accrue calcium, other tissues such as the vascular system become vulnerable to its accumulation in the form of metastatic calcification. Indeed, it has been demonstrated that a greater degree of arterial calcification in those patients with adynamic osteodystrophy is also evident in patients with low bone turnover.373

Strength of Evidence

Calcium kinetic studies clearly show that adult CKD Stage 5 patients with adynamic bone disease have decreased calcium accretion in bone, despite the fact that intestinal calcium absorption is similar in these patients and those with high bone turnover.207 There are no controlled studies on treatment of adynamic bone disease, though its consequences are troublesome. Indeed, more severe growth retardation has been described in those children that developed adynamic bone after treatment with calcium-containing binders and intermittent calcitriol therapy. Recommendations for therapy should be of the current understanding of the pathogenetic mechanisms of the bone abnormalities as well as the abnormalities of the growth plate described in experimental models of adynamic bone.

Bone densitometry and its relationship to fracture is incompletely defined in adult CKD Stage 5 patients, though data continue to suggest that bone density is reduced and fracture rates increased. In the healthy population, there is a strong association between decreased bone density and fractures. While adult patients with osteoporosis and normal renal function benefit from treatment with intermittent PTH injections, it is not clear whether this approach would be effective in the context of CKD Stage 5. Furthermore, treatment with daily PTH injections should not be pursued in pediatric patients with CKD due to the risk of osteosarcoma, which was observed in rats treated intermittently with extremely high doses of synthetic PTH (see package insert, Forteo™, Lilly Laboratories).

Limitations

Much of the data described above suggest a relationship between relatively low PTH levels, bone mass, and low bone turnover in the adult dialysis population, leading to an increased risk for fractures. In addition, a greater degree of arterial calcifications has been described in adult patients treated with hemodialysis and adynamic bone. However, there are no published data of increased fracture rate in children, but adynamic bone disease appears to be associated with further impairment in longitudinal growth in children with CKD Stage 5 after treatment with calcium-containing binders and intermittent calcitriol therapy.312

Clinical Application

Adynamic bone should be treated by increasing bone turnover by allowing the serum PTH concentration to rise to 200-300 pg/mL. This can best be accomplished by discontinuation of the use of active vitamin D analogs and lowering doses of calcium-based phosphate binders as described in Guideline 8. The lowering of bath calcium (1.0-2.0 mEq/L) has also been suggested as a possible approach. One published study of this therapy in a small number of adult patients undergoing peritoneal dialysis did lead to a substantial increase in PTH levels366; however, this approach must be considered experimental at this point. Furthermore, the use of non-calcium, non-metal containing phosphate binders should be considered in those patients especially with evidence of vascular calcifications, in order to diminish the potential role of the exogenous calcium load in its progression.

Recommendations for Research

The long-term safety of lower dialysate calcium concentration for treatment of adynamic bone disease needs to be carefully studied. The use of new phosphate binders should be carefully studied in pediatric patients with CKD. Moreover, agents with a potential to increase bone turnover such as rhGH or PTH need to be studied for the treatment of adynamic bone disease in children with CKD Stage 5. Manipulation of the calcium receptor with either calcilytics (which stimulate PTH release and are not yet FDA approved) or calcimimetics (which suppress PTH, but may lead to intermittent PTH release) may also become an important therapeutic approach.