Place des nouveaux traitements de l'ostéodystrophie rénale : dérivés 1α-hydroxylés de la vitamine D « non hypercalcémiants », complexants non calciques, non magnésiens et non aluminiques des phosphates, et calcimimétiques

Abstract

Molecular biology has recently evidenced that activation of parathyroid calcium receptor was preponderant on that of vitamin D receptor in suppressing parathyroid hormone (PTH) secretion and synthesis and preventing parathyroid hyperplasia. Furthermore, whereas calcium receptor gene deletion is lethal, the hyperparathyroidism and mineralization disorders induced in mice by vitamin D receptor gene deletion can be controlled simply by increasing the calcium/phosphate ratio in the diet to 2. Thus there is no more dogmatic justification for increasing serum calcitriol to supraphysiological levels in spite of the induction by uremia of a resistance to vitamin D. This is all the more less justified that parathyroid cell may produce in situ calcitriol, provided serum calcidiol is sufficient, so that synthesis of PTH may be decreased at its transcriptional step. These new physiopathological mechanisms justify to prevent early hyperparathyroidism (as soon as creatinine clearance decreases below 60 ml/min) by very simple means: supplementation of vitamin D2 or D3 or of their 25 hydroxylated metabolites in order to have a sufficient serum concentration of 25 OH vitamin D (≥ 30 ng/dl) and oral calcium supplement given with the meals for both, compensating the calcium deficiency induced by the dairy product restriction (prescribed for limiting phosphate intake), and for complexing phosphates. The only limitation for this calcium supplement is the increase of albumin corrected serum calcium above 2.37 mmol/l. It is only when this rational basic treatment fails to maintain serum concentrations of Ca, PO 4 and PTH below the upper limit of their optimal ranges recommended by the NKF-K/DOQI that 2 additional alternative therapeutical strategies may be considered: 1) Use of non-calcium-based oral phosphate binder (or nicotinamide which decreases sodium dependent phosphate absorption) + 1α-hydroxylated vitamin D derivatives; 2) Use of calcimimetics (cinacalcet) + increase of calcium load by the Ca-based- oral phosphate binder (and/or the dialysate if the patients is on dialysis). These 2 alternatives are justified by the facts that: 1) 1α-OH vitamin D can be used without hypercalcemic and hyperphosphatemic hazards only when combined with non-calcium-based oral phosphate binder; 2) Calcimimetics suppress PTH by sensitizing the parathyroid calcium receptor to extracellular calcium and induce an hypocalcemia which should be corrected by oral calcium and not by 1α-OH vitamin D in order to better control the hyperphosphatemia. This is particularly important in predialysis patients because in these patients the cinacalcet-induced PTH decrease is associated with an increase in serum phosphate because of increased phosphate tubular reabsorption.