OPTIMAL USE OF 1-ALPHA HYDROXY VITAMIN-D3 DERIVATIVES IN RENAL OSTEODYSTROPHY

1. 1 alpha(OH) vitamin D-3 derivatives have an inconstant long term in hibitory effect on PTH secretion. As a matter of fact they act by thre e mechanisms, one of these being antagonistic: 1) a direct inhibitory action on the prepro-PTH gene; 2) an indirect inhibitory action by inc reasing plasma calcium; 3) an indirect stimulatory action by increasin g plasma phosphate. These two latter phenomena are due to the stimulat ion of the intestinal absorption of these ions as well as to an intrin sic osteolytic action which may override the inhibition of the bone re lease of these ions in relation with the decrease of the PTH plasma le vels. 2. The use of 1 alpha(OH)D-3 derivatives in patients on chronic dialysis is justified in about 30% of the patients on dialysis when in spite of native vitamin D repletion and adequate predialysis control of plasma calcium (2.5 +/- 2 mmol/l) and of plasma phosphate (1.4 - 1. 7 mmol/l), the PTH plasma levels are 3 or 5 fold the upper limit of no rmal wether the patient is on hemodialysis or on CAPD. When hyperphosp hatemia is > 1.7 mmol/l it is first necessary to correct it by the use of higher doses of alkaline calcium salts given with the meals as pho sphate binder together with a negative perdialytic calcium balance ind uced by a lower dialysate calcium in order to avoid hypercalcemia. Con trol of hyperphosphatemia is indeed a necessary prerequisite for the l ong term PTH suppressive efficacy of 1 alpha OH vitamin D derivatives. 3. The use of 1 alpha(OH)D-3 derivatives in the treatment of the pred ialysis uremic patients is even more limited because there is no addit ional mean to decrease the risk of hypercalcemia when oral calcium is used as phosphate binder because of the danger of aluminum and magnesi um phosphate binders. Fortunately in the adult, oral calcium used as p hosphate binder in association with phosphate restriction and correcti on of possible vitamin D depletion and acidosis is usually efficace to control hyperparathyroidism without 1 alpha OH vitamin D-3. This is n ot the case in the child to whom protein and phosphate restriction sho uld not be prescribed because of its incompati ility with the Recomman ded Diet Allowance. Fortunalety the high remodeling rate of his growin g bones, decreases the risk of hypercalcemia due to the combination of CaCO3 and 1 alpha OH vitamin D-3. Because uremic bone resistance to P TH increases with the severity of renal insufficiency, the optimal ran ge of plasma intact PTH is lower before than on maintenance dialysis. They have been estimated to be 0.5 - 1.5, 1-2 and 1.5 - 3 fold the upp er limit of normal for creatinine clearances of respectively above 30, between 30 and 10 and below 10 ml/min/1.73 m(2). 4. There is no compa rative <<long term>> study between calcitriol and alphacalcidol as reg ards the control of the hyperparathyroidism in renal failure. In spite of theoretical speculations there is up to now no safe clinical evide nce neither for the superiority of any parental administration compara tively to the oral administration nor for the intermittent bolus admin istration relatively to a continuous daily treatment. The only obvious advantage of the intermittent parenteral or oral administration versu s the daily oral administration of these drugs is that its compliance may be verified the day on dialysis. 5. Further controlled clinical tr ials are needed in order to precise the place of the less hypercalcemi c and less hyperphosphatemic vitamin D derivatives (24.25 (OH)(2)D-3, 22 oxa-calcitriol, ...), as well as the place of the calcium mimetics, which stimulate the membrane calcium receptors of the parathyroid and type C thyroid cells. 6. The limits of the medical parathyroidectomy once the hyperparathyroidism is overt stress the importance of an earl y prevention of hyperparathyroidism based mainly on the implemented us e of alkaline salts of calcium taken with the meals as phosphate binde r, and of an adequate timing of the surgical parathyroidectomy.