NKF KDOQI GUIDELINES

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

GUIDELINE 13. TREATMENT OF BONE DISEASE IN CKD

The therapeutic approach to bone disease in CKD is based on its specific type. As such, this Guideline encompasses 3 parts: Guideline 13A deals with high-turnover and mixed bone disease; Guideline 13B with osteomalacia; and Guideline 13C with adynamic bone disease.

GUIDELINE 13A. HYPERPARATHYROID (HIGH-TURNOVER) AND MIXED (HIGH-TURNOVER WITH MINERALIZATION DEFECT) BONE DISEASE

13A.1 In CKD patients (Stages 3 and 4) who have plasma levels of intact PTH >70 pg/mL (7.7 pmol/L) (Stage 3) or >110 pg/mL (12.1 pmol/L) (Stage 4) on more than 2 consecutive measurements, dietary phosphate intake should be restricted. If this is ineffective in lowering plasma PTH levels, calcitriol, (EVIDENCE) or 1 of its analogs [alfacalcidol (EVIDENCE) or doxercalciferol (OPINION)] should be given to prevent or ameliorate bone disease. (See Guideline 8A.)

13A.2 In CKD patients (Stage 5) who have elevated plasma levels of intact PTH (>300 pg/mL [33.0 pmol/L]), calcitriol (EVIDENCE) or 1 of its analogs (doxercalciferol, alfacalcidol, or paricalcitol) (OPINION) should be used to reverse the bone features of PTH overactivity (ie, high-turnover bone disease), and to treat defective mineralization. (See Guideline 8B.)

Background

Numerous studies have shown that high-turnover bone (encompassing both osteitis fibrosa and mixed uremic osteodystrophy) is often associated with serum levels of intact PTH of over 400 pg/mL (44.0 pmol/L), though high-turnover lesions may be seen at lower intact PTH levels and low-turnover bone disease may occur at serum levels of intact PTH above 400 pg/mL (44.0 pmol/L).

Rationale

The understanding of bone disease in CKD has evolved dramatically over the years. The recognition that hyperparathyroidism is a complication of kidney failure actually predated, by many years, the initiation of dialysis treatment. Early studies of osteodystrophy focused largely on understanding the pathophysiology and the prevention of hyperparathyroidism. The development of increasingly more precise and specific PTH assays permitted more careful studies of the calcium and PTH interaction and the importance of phosphate in this interaction.

Strength of Evidence

Bone Histology Studies. Initial bone histological studies in the 1960s and 1970s demonstrated the heterogeneity of bone abnormalities. Generally, 2 patterns were described: osteomalacia and osteitis fibrosa. Osteomalacia, characterized by large amounts of unmineralized osteoid, strongly resembled the picture seen in severe vitamin D deficiency. With the demonstration of the critical role of the kidney in vitamin D metabolism, it was thought that the synthesis of the active form of vitamin D would provide the answer to this abnormality. Osteitis fibrosa, in contrast, had been long identified with primary hyperparathyroidism in the general population and the features seen in dialysis patients were quite typical of what had been described in that setting—increases in osteoclasts, osteoblasts, osteocytes, and fibroblasts resulting in abnormal bone resorption, abnormal bone formation, and marrow fibrosis. It was assumed that suppression of PTH would resolve that problem. Ultimately, 2 other histological lesions were described: (1) the adynamic form, characterized by suppressed bone formation with various degrees of bone resorption; and (2) mixed uremic osteodystrophy, with various degrees of mineralization defect and hyperparathyroid bone changes. Mixed uremic osteodystrophy can also be considered a variant of hyperparathyroid bone disease. In summary, there is a continuous spectrum of abnormalities from low-turnover, adynamic bone lesions at one extreme to the high-turnover, osteitis fibrosa lesions at the other.
PTH Studies. Early studies evaluating PTH were compromised by the imprecise nature of early assays, which measured the carboxy-terminal portion of this 84-amino-acid polypeptide. The C-terminal assays were particularly flawed in kidney failure, because of the accumulation of fragments that are normally excreted by the kidney. Subsequently, an amino-terminal assay was more accurate in reflecting high values, but was less effective in discriminating low values. In recent years, the "intact" PTH assay has proven superior to previous assays. Correlations with bone histology, largely carried out over the past decade, have shown it to be better predictive of pathological findings, and to be the best "noninvasive" marker of bone turnover.

Because of the difficulty and expense of obtaining bone biopsies, most clinical studies of osteodystrophy have utilized the levels of PTH, particularly intact PTH, as a marker for bone turnover. Thus, the newer vitamin D analogs have largely obtained FDA approval for use in the control of intact PTH and do not have adequate data to document their effect on bone histology. Limited data do exist to show that features of hyperparathyroid bone disease (osteitis fibrosa) are improved by both oral and parenteral calcitriol. Since intact PTH levels correlate with bone turnover, it was assumed that avoidance of very high or very low intact PTH levels would prevent either the hyperactive osteitis fibrosa or the hypoactive adynamic disorder, though no convincing outcome studies proved this. Indeed, it has been shown recently that the intact PTH assays measure not only PTH-(1-84) but also large C-terminal fragments, some of which antagonize the effects of PTH-(1-84) on bone.

Limitations

See the corresponding section in Guidelines 8A and 8B.

Recommendations for Research

Studies are needed to evaluate the changes in bone histology, PTH, and its fragments with the available vitamin D analogs and other therapeutic approaches.