Nephrol Dial Transplant (2002) 17 [Suppl 11]: 20–22
Treatment of secondary hyperparathyroidism with vitamin D
derivatives and calcimimetics before and after start of dialysis
Tilman B. Drüeke
Inserm Unit 507 et Service de Néphrologie, Hôpital Necker, Paris, France
Abstract
Chronic renal failure is almost always associated
with secondary uraemic hyperparathyroidism. Action
should be taken as early as possible to avoid it or
reduce its severity in patients with chronic kidney
disease (CKD). Over the last decade, the most effective
way of achieving this has been defined as therapy with
active vitamin D derivatives. However, the so-called
‘non-hypercalcaemic’ vitamin D derivatives, which are
said to be superior, have not met our expectations so
far. In contrast, calcimimetic agents, the new class of
compounds that act specifically on the calcium-sensing
receptor, are very promising for the treatment and
prevention of hyperparathyroidism. CKD is associated
with disturbances in calcium, phosphate, and vitamin
D metabolism that occur early in the course of renal
disease. In most patients, these disturbances lead to
secondary hyperparathyroidism and osteitis fibrosa
or associated, more complex, skeletal lesions. Here, we
focus on recent advances in the prevention and treat-
ment of secondary hyperparathyroidism by vitamin D
derivatives and by calcimimetic agents.
Keywords: anaemia; calcimimetics; chronic kidney
disease; secondary hyperparathyroidism; vitamin D
derivatives
Active vitamin D derivatives
Nephrologists should aim for early treatment and, if
possible, prevention of secondary hyperparathyroid-
ism, taking into account the underlying pathogenetic
mechanisms. In incipient renal failure, patients should
be advised to take sufficient but not excessive
Correspondence and offprint requests to: Dr Tilman B. Drüeke,
Inserm Unit 507, Hôpital Necker, 161 rue de Sevres, F-75743 Paris
Cedex 15, France. Email: drueke@necker.fr
# 2002 European Renal Association–European Dialysis and Transplant Association
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supplementary calcium. If there is a tendency towards
low plasma calcium and phosphorus, oral calcidiol
(25-OH vitamin D), calcitriol, alfacalcidol, or other
active vitamin D derivatives, which are described
below, can be prescribed to prevent osteitis fibrosa or
osteomalacia. There are well-established ways of using
1a-hydroxylated vitamin D derivatives. There is no
proven difference in efficacy between oral and intra-
venous (i.v.) administration of these compounds, or
between daily and intermittent administration [1–6].
Plasma, ‘intact’ parathyroid hormone (iPTH) should
be in the upper range of normal. In pre-dialysis
patients, the target iPTH level remains to be defined.
Based on clinical experience, but not on hard evidence,
the target level should increase progressively with
decreasing renal function [7]. In dialysis patients, iPTH
levels of two to three times the upper normal range
appear reasonable. Only about 50–60% of iPTH
detected by current iPTH assays is ‘true’ iPTH, con-
taining the full 84 amino acids. A recently developed
immunoradiometric assay detects full-length, ‘true’
human iPTH, but not amino-terminally truncated
fragments [8]. It remains to be seen whether this
new assay is more clinically useful for the diagnosis
and treatment of overactive parathyroid tissue than
well-established measurements of iPTH.
Highly active 1a-hydroxylated vitamin D derivatives
can easily induce hypercalcaemia and aggravate hyper-
phosphataemia. Recent, intensive research has focused
on developing non-hypercalcaemic vitamin D ana-
logues, including the natural vitamin D compound
24,25-(OH)2 vitamin D3, 22-oxa-calcitriol (OCT),
19-nor-1,25-(OH)2 vitamin D3 (paracalcitol), hexa-
fluorocalcitriol, and 1a-OH vitamin D2 (doxecalciferol)
[9–12]. Numerous large studies have failed to show
that the novel agents entirely avoid hypercalcaemia
or hyperphosphataemia, and none is demonstrably
superior to calcitriol or alfacalcidol in patients with
uraemia in the long term. Extended experience with
these agents is needed, as are direct head-to-head com-
parisons with parent compounds, before new vitamin
D derivatives can be accepted as more clinically useful
Use of vitamin D derivatives and calcimimetics in secondary hyperparathyroidism
than those already in use. None has, as yet, a definitive
place in routine treatment.
In dialysis patients with measured vitamin D
deficiency, calcidiol may be a valuable alternative to
1a-hydroxylated vitamin D derivatives [13].
Until very recently, high doses of oral calcium
supplements anduor 1a-hydroxylated vitamin D deriv-
atives were the mainstay of prevention and treatment
of secondary hyperparathyroidism in patients with
chronic kidney disease (CKD). However, although
large amounts of calcium salts effectively control
hyperphosphataemia and an overactive parathyroid,
this treatment may not be as well tolerated as first
thought, because of the associated soft-tissue calci-
fication [14,15]. The same applies to high doses of
vitamin D derivatives [16]. Therefore, nephrologists
are eagerly awaiting new vitamin D-derived com-
pounds that do not increase intestinal absorption of
calcium and phosphate.
Of the calcium- and aluminium-free compounds, the
recently introduced phosphate binder sevelamer may
become a new therapeutic option [17,18].
Calcimimetics
Calcimimetics, which specifically activate the calcium
receptor, look promising. In the first, acute 2-day
study, in patients with mild hyperparathyroidism
on long-term haemodialysis, the calcimimetic R-568
reduced plasma iPTH within hours with a rapid
decrease in plasma calcium and no change in plasma
phosphate level [19]. A second, short-term, placebo-
controlled study of R-568 over 15 days in dialysis
patients with severe hyperparathyroidism showed
progressive decline of plasma iPTH levels from base-
line iPTH over the first 9 days of treatment. iPTH
remained below pre-treatment level for the remaining
6 days [14]. Plasma iPTH levels decreased by 60–80%
within 4 h of the first dose, accompanied by a sharp
decrease in plasma calcium levels. Notably, blood
ionized calcium levels fell below 1.0 mmolul in seven of
16 patients receiving R-568. Five patients withdrew
from the study after developing hypocalcaemia, and
three completed treatment after the dose was reduced.
In several short- and long-term studies in rats with
CKD, R-568 prevented significant parathyroid hyper-
plasia [20,21] and reversed osteitis fibrosa [22].
In 2000 and 2001, several phase II studies evaluated
oral administration of the calcimimetic agent AMG-
037 in patients with secondary hyperparathyroidism
on chronic haemodialysis. AMG-037 has more predict-
able metabolism in patients with CKD than R-568.
Preliminary results were reported at the annual
meeting of the American Society of Nephrology in
San Francisco, USA, in October 2001 [23]. Patients
(ns215) in three separate 12-week titration studies
received either AMG-037 or placebo. Eligible patients
had plasma iPTH levels P300 pguml and plasma total
calcium concentrations between 2.2 and 2.75 mmolul.
21
All patients received an initial daily oral dose of 20 mg
(trials 1 and 2) or 25 mg (trial 3), subsequently
increased step-wise to a maximum of 50 mg (trials 1
and 2) or 100 mg (trial 3), based on plasma iPTH
response and safety considerations. After week 12, the
dose was kept constant during a long-term follow-
up study, which is ongoing. At week 12, the plasma
iPTH level had decreased by an aggregate mean of
24% in patients on AMG-037 and increased by 16%
in the combined placebo group. Similarly, the plasma
calcium 3 phosphorus (Ca 3 P) product reduced by
an aggregate mean of 7.4% in AMG-037-treated
patients and increased by 14% in the placebo-treated
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patients. The drug was well tolerated, with no marked
differences in side effects between the two groups.
Thus, with this new class of agents that enhance
the sensitivity of the calcium receptor for extracellular
calcium, it appears possible for the first time to
decrease both plasma iPTH and the Ca 3 P product.
To date, the only clinical experience with calcimimetics
in renal failure patients has been in patients with end-
stage renal disease. We hope the drugs will soon be
tested in large clinical trials in pre-dialysis patients
since, ideally, they should be given early in CKD to
prevent development of parathyroid over-activity.
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