Prevention of metabolic bone disease in the pre-end-stage renal disease setting

Abstract

The methods for preventing hyperparathyroid bone disease, the major variety of renal osteodystrophy, from developing in patients with renal impairment are reviewed. With far-advanced chronic renal failure (creatinine clearance [CCr] < 15 to 20 ml/min), when many of these patients are seen by nephrologists, the use of diets very low in protein, and hence also very low in phosphorus content, combined with calcium-containing phosphate binders, have been shown to lower serum intact PTH levels and improve the osseous pathology. However, the degree of dietary restriction required to achieve success may be quite difficult to follow by most patients encountered in clinical practice. In less-advanced renal insufficiency (CCr, 25 to 60 ml/min), the active vitamin D sterols calcitriol or alfacalcidol [1 alpha-hydroxyvitamin D3] have been shown to ameliorate the skeletal lesions of renal osteodystrophy. The results of six double-blind, placebo-controlled studies and five major open-labeled studies with calcitriol or alfacalcidol are reviewed. Skeletal biopsies were improved and sometimes normalized by using calcitriol or alfacalcidol in daily doses of 0.25 to 0.5 microgram/d, and the incidence of hypercalcemia was quite low with these doses. When the dosage was increased in one study, there was a higher incidence of hypercalcemia. Improved bone mineral density of the spine and hip was reported after 1 yr in calcitriol-treated patients compared with results in the placebo group. Another report documented more favorable intact PTH suppression with intermittent dosing of 2.0 micrograms given either once or three times weekly compared with daily dosing (0.5 microgram/d); there was no rise of serum Ca over the 3-mo trial with any protcol. Other data support the greater likelihood of having normal bone if treatment is initiated when CCr exceeds 25 ml/min. There was no risk of more rapid progression of renal insufficiency in any of the studies reviewed, which include 242 patients who were given an active vitamin D sterol. One trial that used a calcitriol dose of 0.5 microgram/d noted a fall in CCr and a rise in serum creatinine, but true GFR (inulin clearance) did not change. A calcitriol-induced reduction of tubular creatinine secretion is suggested. The risk of inducing low bone turnover (adynamic bone) seems to be quite low with 10.4% of alfacalcidol-treated patients versus 6.5% of placebo developing this "lesion" after 2 yr. Despite the lack of Food and Drug Administration approval for use of these sterols in the predialysis state, evidence is compelling that: there are benefits in retarding the development or progression of metabolic bone disease; there is minimal risk, providing that low doses are used; and there is close monitoring of serum Ca, P, and creatinine. The optimal benefits may be obtained if this treatment is started early in the course of renal insufficiency (CCr in the range of 25 to 60 ml/min).