Current treatment options in secondary hyperparathyroidism.

Sir, We read with interest the article by Reichel [1] in the January issue of NDT entitled ‘Current treatment options in secondary hyperparathyroidism’ and the algorithm suggesting that calcimimetics be used as first-line therapy while minimizing the use of vitamin D analogues. Since secondary hyperparathyroidism (28HPT) remains a problem in patients treated with maintenance dialysis, we share the author’s enthusiasm for the newly developed calcimimetic agents as a promising therapeutic option. However, we would urge caution in dispensing with the use of active vitamin D sterols as first line therapy, since in addition to being a safe and effective means of controlling 28HPT, these sterols have an important role in maintaining bone health and cardiovascular function in the general population as well as in patients treated with dialysis. Vitamin D sterols have both genomic and non-genomic actions in many tissues, including parathyroid gland, intestine, heart and bone. In patients treated with dialysis, absence of renal 1 -hydroxylase results in low-systemic calcitriol levels. In such individuals, therapy with vitamin D sterols restores intestinal calcium absorption, suppresses parathyroid hormone levels, improves cardiac function [2], and suppresses osteoblastic activity [3]. The induction of hypercalcaemia, hyperphosphataemia and adynamic bone during the treatment of 28HPT has raised concerns about the safety of high doses of vitamin D sterols; however, these adverse effects have been described primarily in patients treated with calcium-based phosphate binders in conjunction with vitamin D analogues. Recent data from large cohorts of patients treated with non-calcium containing phosphate binders have consistently demonstrated that higher doses of vitamin D can be used without increasing serum calcium levels [3,4]. Furthermore, sevelamer and vitamin D are as effective as vitamin D plus calcium carbonate in suppressing parathyroid hormone (PTH) and controlling of the skeletal lesions of 28HPT, without inducing adynamic bone or altering serum calcium and phosphorus levels [3]. Treatment with active vitamin D sterols has been used for 30 years to control 28HPT in both adults and children as well as to improve growth in uraemic children, while the burden of calcification increases during the treatment with calcium carbonate plus vitamin D [4]. Active vitamin D sterols have also been shown to improve cardiac function in dialysed patients with severe 28HPT [2], and cross-sectional trials from large dialysis databases have demonstrated a survival advantage in patients treated with active vitamin D sterols over those who are not receiving any vitamin D. This survival benefit was consistent over all levels of calcium, phosphorus and PTH [5]. While these results are compelling, further prospective, randomized trials are needed to substantiate these observations. Clinical observations and basic research also support an essential role for active vitamin D sterols in normal bone biology. Treatment with active vitamin D sterols has been used for 30 years to control 28HPT in both adults and children as well as to improve growth in uraemic children [6]. Indeed, Panda et al. [7] have recently demonstrated that active vitamin D sterol is essential for proper growth plate morphology. While mice lacking the vitamin D receptor (VDR) (although with high levels of endogenous calcitriol) had an altered growth plate morphology that could be rescued with a high calcium and lactate diet, mice lacking 1 -hydroxylase, (and, hence, calcitriol) had skeletal abnormalities that could not be corrected with a high calcium and lactate intake [7]. These findings suggest that active vitamin D sterols are essential for normal bone biology, that these actions are mediated by a receptor other than the VDR, and that correction of calcium and phosphorus metabolism alone is insufficient to normalize bone in the absence of vitamin D. Recent evidence indicates that 25(OH) vitamin D stores are low in a large portion of the general population, and that chronic kidney disease is a risk factor for this deficiency [8]. However, while in the general population low levels of 25(OH)D have been associated with increased PTH levels and supplementation with control of 28HPT [9], the impact, in patients treated with dialysis, of restoring 25(OH) vitamin D stores remains to be determined. In patients undergoing dialysis, promising benefits from the use of calcimimetics have been demonstrated, including a lowering of serum calcium, phosphorus, the calcium phosphorus product, and PTH levels. Moreover, a retrospective analysis of these data has shown a decrease in fracture rate, decrease in the rate of hospitalization for cardiovascular events, decrease in the rate of parathyroidectomy and improvement in quality of life in patients treated with calcimimetics [10]. However, these data were obtained from patients with persistent 28HPT—two-thirds of whom received vitamin D analogues and over half of whom received calcium-based phosphate binders during therapy. Current data indicate that calcium-sensing receptor expression is up-regulated by vitamin D sterols [11], suggesting that treatment with vitamin D may be necessary for optimal effect of calcimimetic agents. While we are encouraged by the studies demonstrating the usefulness of calcimimetic agents in the management of 28HPT, we would urge caution in eliminating the use of active vitamin D sterols as first-line therapy, since they are a safe and effective means of suppressing PTH and are associated with cardiac and skeletal benefits in dialyzed patients. The role of 25(OH) vitamin D in the treatment of renal osteodystrophy (ROD) is as yet unclear, but may also play an important role. Since the current data on calcimimetics are limited to trials in which the majority of patients also received vitamin D sterols, long-term prospective trials are warranted before the routine use of calcimimetics is adopted as first-line therapy for dialysed patients.