1-Alpha-Hydroxyvitamin D₃Derivatives in the Treatment of Renal Bone Diseases: Justification and Optimal Modalities of Administration

Abstract

The use of 1 α-hydroxyvitamin D3 [ 1 α(OH)D3] derivatives in a uremic patient is justified only in the treatment of hyperparathyroidism (i.e. when plasma intact parathyroid hormone -PTH – levels are above five or three times the upper limit of normal according to whether the patient is on continuous ambulatory peritoneal dialysis or on hemodialysis and between 0.5-1.5, 1-2 and 2-3 times the upper limit of normal for a creatinine clearance of, respectively, 30, between 30 and 10, or below 10 ml/min/1.73m²). The following prerequisites have however to be satisfied: (1) a good vitamin D3 repletion should be secured by plasma 25(OH)D levels of 20-30 ng/ml (if necessary by administration of native vitamin D or 25(OH)D3), and (2) phosphate retention (which is aggravated by the increased phosphate intestinal absorption induced by the 1α(OH)D derivatives) and the consequent possible hyperphosphatemia should be prevented or corrected by the oral administration of alkaline salts of calcium given before the meals as phosphate binders without inducing hypercalcemia. These prerequisites explain the narrow therapeutical margin of lα(OH)D₃ derivatives in uremic patients before dialysis (more so in the adult than in the child) and the possible broadening of this margin in the patients on dialysis by the use of low dialysate calcium concentrations (1.25-1.00 mmol/l) in order to prevent hypercalcemia by inducing a negative perdialytic calcium balance. Once hyperphosphatemia is prevented by oral calcium, 1α(OH)D₃ derivatives have the advantage to suppress the transcription of the prepro PTH gene by a mechanism independent of an increase in plasma calcium. Controlled randomized trials have not confirmed the claimed advantage in efficacy and safety of the parenteral versus the oral route nor of the intermittent versus the daily mode of their administration. The advantages of using the so called ‘nonhy-percalcemic hyperphosphatemic’ vitamin D3 derivatives in combination with oral calcium over 1α(OH)D3 derivatives in the treatment of uremic hyperparathyroidism are still waiting for clinical demonstration. Vitamin D derivatives have no place in the treatment of aluminic bone diseases which necessitate long term deferoxamine treatment and prevention of aluminum exposure by the dialysate and the phosphate binders. They are not indicated in the treatment of’idiopathic’ adynamic bone disease which is due to uremia per se combined with an excessive PTH suppression for the degree of renal failure. This low bone turnover pattern is associated with an increased risk of hypercalcemia and hyperphosphatemia and necessitates only a stimulation of PTH secretion by inducing a negative calcium balance with a lower dialysate calcium concentration or simply by discontinuing the oral calcium supplement in the uremic patient not yet dialyzed. In rare cases this pattern is due to a granulomatosis and is corrected by prednisone.

Secondary Hyperparathyroidism in Severe Chronic Renal Failure Is Corrected by Very-Low Dietary Phosphate Intake and Calcium Carbonate Supplementation

“…Therefore, correction of hyperphosphatemia and hypocalcemia by lowering dietary phosphorus intake and by the administration of calcium-containing phosphate binders is the first target of therapeutic intervention [4], whereas the use of vitamin D derivatives is questionable, in predialysis patients at least [5]. …”

Total parathyroidectomy with autotransplantation in patients with renal hyperparathyroidism: indications and surgical approach

“…Hypercalcemia also strengthens the indication for surgery in RH. 7,9,13 In our series, 25 patients had hypercalcemia; while 30 patients had hyperphosphatemia. The clinical effects of RH that was refractory to medical treatment were: pruritus, bone and joints pain, muscle weakness, progression of soft tissue calcification, and spontaneous fractures.…”

“…7 Several medical therapeutic options for SHPT are currently available, aiming at reducing hyperphosphatemia, elevate serum calcium, reduce PTH, and improve skeletal turnover. [7][8][9] For example, the administration of calcium supplements in the form of calcium carbonate or calcium acetate can be effective for managing PTH levels in some dialysis patients or in those with early stages of renal failure. 10,11 Administration of vitamin D (calcitriol) also constitutes a promising form of prophylaxis and treatment of SHPT, while for those patients in whom dietary restriction is not sufficient to control serum phosphorus levels, phosphate-binding agents must be prescribed.…”

“…12 However, several studies have demonstrated that most patients with excessively increased PTH levels values fail to respond to vitamin D treatment and surgical treatment is required. 9,13 Parathyroidectomy can dramatically lower PTH and phosphate levels, but is typically reserved for patients with refractory secondary and tertiary hyperparathyroidism. 14 In about 10-30% of patients in hemodialysis for more than 10 years, parathyroidectomy is required.…”

Intravenous Alfacalcidol Once Weekly Pulse Therapy for Secondary Hyperparathyroidism in Hemodialysis Patients

“…6 Alfacalcidol (1-a-OH-VD) has been demonstrated to be a good metabolite with the capacity to downregulate parathyroid gland activity, with scant hypercalcemic potential when used at doses adjusted to the degree of SHPT in hemodialysis (HD) patients. [7][8][9] Nevertheless, the difficulties in controlling the disease in clinical practice constitute a problem for adhering to the treatment recommendations. Based on this fact, we conducted an observational, prospective study in chronic HD patients with high i-PTH levels to evaluate the efficacy and safety of IV administration of a high dose of alfacalcidol once weekly versus thrice weekly.…”