Arising from: Bushinsky DA (2007) Optimal paricalcitol starting dose for parathyroid hormone suppression in secondary hyperparathyroidism. Nat Clin Pract Nephrol 3: 12–13 doi:10.1038/ncpneph0363

Author’s response: Bushinsky DA (2007) Optimal paricalcitol starting dose for parathyroid hormone suppression in secondary hyperparathyroidism. Nat Clin Pract Nephrol doi:10.1038/ncpneph0449

In a Practice Point published in the January issue of Nature Clinical Practice Nephrology, David A Bushinsky carefully pointed out that the vitamin D status of patients recruited in the study by Mitsopoulos et al. 1 was unknown. As a next logical study of how to achieve more-rapid parathyroid hormone (PTH) suppression with lower risks of inducing adynamic bone disease and elevating Ca × P product, he proposes use of cinacalcet combined with perdialytic administration of a more physiologic amount of the deficient hormone calcitriol (1,25[OH]2-vitamin D; e.g. 0.5 µg) or of its less hypercalcemic derivative paricalcitol (2 µg). To assess the efficacy of this approach, he proposes measuring more clinically relevant parameters, such as vascular calcification, cardiovascular events and/or mortality. We totally agree with these ultimate goals of therapy, but we would like to suggest a safer and more cost-effective therapeutic approach. Instead of calcitriol or paricalcitol, we would suggest using plain vitamin D3 (cholecalciferol) or 25OH-vitamin D3 to correct vitamin D insufficiency (i.e. serum calcidiol [25OH-vitamin D] levels <75 nmol/l [<30 ng/ml]). Ritter et al. 2 have shown that 100 nmol/l (40 ng/ml) calcidiol is as effective as 100 pmol/l (40 pg/ml) calcitriol in suppressing PTH secretion by parathyroid cells, even when the parathyroid cell 25OH-vitamin D-1α-hydroxylase is inhibited, a situation which might exist in uremic patients because hyperphosphatemia increases levels of fibroblast growth factor 23 (FGF23), a known suppressor of this enzyme.

The prevalence of vitamin D insufficiency in the US dialysis population has been estimated at 97%.3 Correction of this insufficiency in the general elderly population has been proven to decrease the risk of fracture,4 and epidemiological studies have shown that vitamin D deficiency is associated with increased cardiovascular risk and mortality, as well as increased risk of infections and cancer.5

A comparison of two German cohorts of young adults (aged 23–27 years) with childhood-onset end-stage renal disease (ESRD),6 indicated that the prevalence of coronary artery calcification was nine times lower in one (the Berlin cohort7) than the other (the Heidelberg cohort8; 10% vs 92%). PTH suppression was twice as great in the Berlin cohort (155 ng/l vs 364 ng/l), who received a 34-fold lower cumulative dose of 1αOH-vitamin D derivatives and a 7-fold lower dose of calcium carbonate (CaCO3). The key difference in the treatment of these two cohorts was the use in Berlin of a relatively high dose of cholecalciferol (5,700 IU/day), known to produce serum calcidiol levels of 150–275 nmol/l (60–110 ng/ml), whereas in Heidelberg these levels were only maintained above 40 nmol/l (16–20 ng/ml; O Mehls, personal communication). Therefore we suggest that because of uremia-induced resistance to vitamin D, levels of serum calcidiol in dialysis patients (especially growing children) should probably be greater than the level of 100 nmol/l (40±10 ng/ml) presently recommended by the National Kidney Foundation’s 2003 Kidney Disease Outcomes Quality Initiative guidelines for CKD stages 3–4, but paradoxically not for dialysis patients.

Regarding cinacalcet, we would recommend the concomitant use of this agent not with paricalcitol or calcitriol, but rather with CaCO3 as a phosphate binder. In contrast to 1αOH-vitamin D, CaCO3 not only increases serum calcium but also decreases serum phosphate, resulting in lower FGF23 level and higher 25OH-vitamin-D-1α-hydroxylase activity of parathyroid cells, as well as in overexpression of their calcium receptor. Suppression of PTH synthesis will therefore be greater and associated with lower serum phosphate level, without the need for an expensive non-calcium-based phosphate binder. The clinical relevance of these pathophysiological events has been already shown9 by a comparison of two cinacalcet trials, one that used a dose of 50 mg/day and one that used a dose of 100 mg/day. PTH suppression was comparable in the trials, but the serum phosphate reduction was much smaller in the trial that used the higher dose of cinacalcet (2.4% [NS] vs 7%). The only possible explanation for this discrepancy was the introduction of calcitriol or paricalcitol in the cinacalcet arm of this trial and not in the other trial. Of course a controlled trial will be necessary to prove the superiority of our approach over that proposed by Bushinsky.