Secondary hyperparathyroidism (2oHPT) is a common disorder in patients with chronic renal failure.
The increased PTH secretion and parathyroid gland hyperplasia are attributed primarily to the retention of phosphate and the decreased capacity to produce 1,25-dihydroxyvitamin D3 [1,25(OH)2D3].
Low serum 1,25(OH)2D3 reduces intestinal calcium transport, and high serum phosphate further drives down the levels of serum calcium.
The resulting hypocalcemia is a strong stimulus for PTH synthesis and secretion as well as parathyroid gland hyperplasia.
The parathyroid glands respond directly to phosphate and 1,25(OH)2D3 as well.
Phosphate can increase PTH synthesis directly, enhance PTH mRNA stability and stimulate parathyroid gland hyperplasia.
1,25(OH)2D3 inhibits PTH gene transcription and parathyroid hyperplasia.
Initially, the parathyroid responds to the low calcium by increasing PTH secretion and synthesis, but prolonged hypocalcemia, hyperphosphatemia and decreased 1,25(OH)2D3 lead to parathyroid gland hyperplasia.
Thus, the low levels of 1,25(OH)2D3 in these patients enhance PTH gene expression.
The major impact of chronically elevated PTH is on the bone.
PTH stimulates bone turnover, increasing both formation and resorption.
The resulting bone, referred to as woven bone, is of poor quality and easily fractured.
PTH-mediated high turnover bone disease is a major cause of morbidity in renal patients.
Treatment of Secondary Hyperparathyroidism
Prevention and treatment of secondary hyperparathyroidism requires both the control of serum phosphate and the restoration of 1,25(OH)2D3 levels.
Phosphate is commonly controlled by retarding dietary phosphate absorption with the use of phosphate binders.
The most commonly used binders at present are calcium salts.
Replacement therapy with 1,25(OH)2D3 has been shown to aid in the suppression of PTH both by its direct action on the parathyroid glands and by increasing calcium absorption.
However, the therapeutic window for 1,25(OH)2D3 is relatively narrow, with a small separation between the doses that are effective in suppressing PTH and those that elevate serum calcium.
Combining 1,25(OH)2D3 therapy with oral calcium binders further increases the risk of hypercalcemia. Hypercalcemia is especially problematic in renal patients.
It is now clear that the combined increase in calcium and phosphate (Ca x P product) is a key factor in vascular calcification and coronary artery disease, the major cause of mortality in renal failure patients. In addition, hypercalcemia can lead to oversuppression of PTH.
The bone of renal failure patients is resistant to PTH, and reducing serum PTH back to near normal leads to another form of renal osteodystrophy referred to as low turnover or adynamic bone disease, in which the bones fail to remodel sufficiently and gradually lose their strength.
For these reasons, analogs of vitamin D that retain the direct suppressive effect of 1,25(OH)2D3 on the parathyroid glands but that have lower calcemic and phosphatemic activity could provide a safer and more effective means of controlling secondary hyperparathyroidism.
Development of Vitamin D Analogs for Secondary Hyperparathyroidism
Several vitamin D analogs with lower calcemic activity have been examined for their ability to suppress PTH.
The general approach has involved identifying analogs with low calcemic activity that still retained high VDR affinity and the ability to suppress PTH secretion in cultured parathyroid cells.
Many vitamin D analogs with these properties were found to be ineffective in suppressing PTH in vivo for reasons that will be discussed in the subsequent section on mechanisms.
The vitamin D analogs discussed in this section have been proven effective in both experimental animal models and in clinical trials, and three are now approved for use in patients with secondary hyperparathyroidism in renal failure.
22-Oxacalcitriol (OCT)
One of the first analogs shown to exert a selective action on the parathyroid glands was 22-oxa-1,25(OH)2D3 (22-oxacalcitriol or OCT).
Developed by Chugai Pharmaceuticals in Japan,OCT differs from 1,25(OH)2D3 only by substitution of an oxygen in place of carbon 22 in the side chain.
OCT was reported to have very low calcemic activity in experimental animals, yet could potently differentiate leukemia (HL-60) cells in vitro.
OCT also mimicked 1,25(OH)2D3 in the suppression of PTH secretion in vitro in cultures of bovine parathyroid.
The mechanism for PTH suppression by OCT was similar to that of 1,25(OH)2D3 in that the analog decreased PTH mRNA to the same extent (60 to 80%) as 1,25(OH)2D3 in normal rats, suggesting that it was also acting at the level of gene transcription.
Furthermore, the mRNA levels were measured 48 hours after injection of a relatively small dose (40 ng); the significance of this prolonged suppression with respect to the mechanism of the selectivity of OCT is discussed below.
Studies in animal models of renal failure demonstrated the greater therapeutic index of OCT in suppressing PTH. In contrast, doses of 1,25(OH)2D3 just above those that suppress PTH produced a significant increase in serum calcium.
Naveh-Many and Silver found that OCT was less active than 1,25(OH)2D3 in lowering PTH mRNA in uremic rats, but that it was much less calcemic indicating a superior therapeutic index.
Similar findings in uremic dogs were reported by Brown and coworkers who showed that a single injection of a noncalcemic dose of OCT could suppress serum PTH for up to 69 hours. The ability of OCT to effectively reduce PTH suggested that it could also ameliorate the high-turnover bone disease.
Hirata et al examined this directly in rats with glycopeptide-induced progressive nephritis that developed osteitis fibrosa over an 8-month period.
The rats were then treated with two fixed doses OCT (0.03 or 0.15 µg/kg body weight) or vehicle three times per week for 15 weeks.
As expected, OCT lowered PTH substantially.
Bone histomorphometry revealed that OCT dose-dependently decreased the rates of both bone formation and resorption and reduced the fibrosis volume of the bone.
At the doses used, there was no hypercalcemia or adynamic bone disease. The effect of OCT on renal osteodystrophy was also examined by Monier-Faugere et al in dogs made uremic by subtotal nephrectomy.
After 14 weeks of renal insufficiency, the dogs were treated 3 times per week with OCT or vehicle for 60 weeks.
In this study, the dose of OCT was adjusted to maximize PTH suppression but to avoid hypercalcemia. OCT signicantly decreased PTH levels.
The analog reversed abnormalities in bone formation, including woven osteoid and fibrosis. However, no change in the rate of bone turnover was observed.
While hypercalcemic episodes occurred, OCT did not induce low turnover bone disease.
Most recently, Tsukamoto et al studied the effect of OCT on bone histology in a small group of patients with severe secondary hyperparathyroidism.
The analog was administered 3 times per week at the end of the hemodialysis session.
After 24 weeks of treatment, OCT reduced PTH modestly (35%) overall, but considerable variation in response was observed; 5 of the 10 patients did not respond to doses that did not produce hypercalcemia, while the other patients showed a PTH suppression of over 50%.
Six patients, 5 of which were responders, agreed to a second, post-treatment bone biopsy.
OCT significantly reduced bone marrow fibrosis, and decreased markers of bone turnover although signficant decreases were seen only in osteoid volume and bone formation rate.
The results of the preclinical and clinical trials indicated that OCT can effectively suppress PTH and is less calcemic than 1,25(OH)2D3.
The relative therapeutic windows of OCT and 1,25(OH)2D3 in patients remains to be established.
OCT was approved in the year 2000 for the treatment of secondary hyperparathyroidism in patients in Japan.
19-nor-1,25(OH)2D2
The promising findings with OCT prompted the development of other analogs for treatment of secondary hyperparathyroidism.
19-nor-1,25(OH)2D2 (19-norD2), developed by Abbott Laboratories in the United States, has also proven to be an effective and safe therapy, and was the first of the new less calcemic vitamin D analog to be approve for use in patients.
This compound lacks the exocyclic carbon 19 and has a vitamin D2 side chain instead of the vitamin D3 side chain of calcitriol.
Initial studies in normal rats showed 19-norD2 to be much less calcemic than 1,25(OH)2D3. Nine daily injections of various doses of 19-norD2 and 1,25(OH)2D3 indicated that 19-norD2 was approximately 10 times less calcemic.
Initial experiments in primary cultures of bovine parathyroid cells, on the other hand, showed that 19-norD2 was equipotent to 1,25(OH)2D3 in suppressing steady-state PTH secretion in vitro.
Preclinical studies performed in uremic rats demonstrated that 19-norD2 effectively suppressed PTH over a wide dose range without inducing hypercalcemia.
Just as important, the analog was found to be less phosphatemic as well.
Analysis of the parathyroid glands of uremic rats treated with 19-norD2 showed that it decreased PTH mRNA, suggesting that the analog suppressed PTH via the same transcriptional repression mechanism as 1,25(OH)2D3.
Treatment with 19-norD2 can both prevent and arrest the development of high turnover bone disease in uremic rats.
Slatopolsky et al reported that prophylactic treatment of uremic rats with 19-norD2 for the first two months following partial nephrectomy largely prevented increases in bone formation rate, unmineralized osteoid, bone resorption and fibrosis.
Of greater clinical relevance, these investigators found that 19-norD2 could reverse the abnormal bone metabolism in rats with chronic renal failure and established parathyroid bone disease. Thus, correction of PTH by 19-norD2 can prevent and correct the PTH-induced high turnover bone disease.
Calcitriol treatment has been shown to block parathyroid hyperplasia in uremic rats, but this effect could have been attributed to the mild hypercalcemia produced at the doses used.
Takahashi et al found that 19-norD2, when administered from the time of induction of renal failure, reduced the rate of parathyroid gland growth in uremic rats, suggesting that it may have utility in preventing or arrresting parathyroid hyperplasia in patients.
The mechanism for the antiproliferative effect of 19-norD2 and calcitriol in the parathyroids is under investigation.
Cozzolino et al reported that both vitamin D compounds, as well as high calcium and low phosphate, suppressed the expression of transforming growth factor alpha (TGFα) and induced the cell cycle inhibitor p21 in the parathyroid glands of uremic rats.
The success of the preclinical studies led to trials in renal failure patients.
Martin et al reported the results of a placebo-controlled, multicenter trial in which 19-norD2 was compared to placebo. After a 4-week washout period, 19-norD2 (or placebo) was administered three times per week after dialysis for 12 weeks.
The dose of 19-norD2 was started at 0. 04 µg/kg and increased by 0.04 µg/kg every two weeks until a target reduction of 30% was achieved.
Of the patients receiving 19-norD2, 27 out of 40 had at least a 30% decrease in intact PTH, compared to 3 of 38 patients receiving placebo.
There was no increase in serum calcium or phosphate before reaching this designated goal.
Out of 414 determinations of serum calcium in the 19-norD2-treated group, only 8 exceeded 11 mg/dl compared to 4 in the placebo group.
These findings demonstrated the efficacy and safety of 19-norD2 in the treatment of secondary hyperparathyroidism. Similar results were reported in other studies.
Llach et al examined the effects of fixed doses of 19-norD2 in a small number of patients.
After a washout period, renal patients received 19-norD2 at 0.04, 0.08, 0.16 or 0.24 µg/kg three times per week after dialysis for 8 weeks, and the 30% target reduction was achieved in 4/6, 1/4, 5/6 and 5/6 of the patients in the four groups, respectively.
Calcium and phosphate changes were not presented for each group, but the combined data showed no signficant effects compared to placebo.
Martin et al determined the dose equivalency of 1,25(OH)2D3 and 19-norD2 in 29 patients that were on a stable dose of 1,25(OH)2D3.
Administration of a 4-fold higher dose of 19-norD2 maintained PTH levels at their suppressed levels with no significant difference between the pre- and post-crossover levels.
Serum calcium and phosphate levels also did not change.
These clinical trials demontrated that 19-norD2 is safe and effective in reducing PTH levels.
This analog, under the name Zemplar, was approved for treatment of secondary hyperparathyroidism in renal failure patients in the United States in 1998.
As with the other analogs, a direct comparison of therapeutic windows for 19-norD2 and 1,25(OH)2D3 in patients has not been published.
1α(OH)D2
The most recent vitamin D analog to become available for renal failure patients is 1α(OH)D2.
This compound is a prodrug and, like its vitamin D3 counterpart alfacalcidol, must be activated in vivo. 1α(OH)D2, developed by Bone Care International in the United States, was tested directly in dialysis patients; studies in experimental animal models of renal failure have not been reported.
The results of a trial in renal failure patients with moderate to severe secondary hyperparathyroidism (intact PTH > 400 pg/ml) was reported by Tan et al After an 8-week washout period, oral 1α(OH)D2 was administered initially at a dose of 4 µg/day or 4 µg thrice weekly, and the dose was adjusted to maintain serum intact PTH levels between 130 and 250 pg/ml.
The target goal was reached by 21 of the 24 patients during the course of the study, although 12 patients reached levels below the target range.
At the end of the study, PTH levels were within the target range in 8 patients, below the 130 pg/ml in 5 patients, and above 250 pg/ml in 11 patients (7 of these had stopped treatment temporarily for dose adjustment).
The rate of response varied, with two patients showing a 50% reduction in PTH within 2 weeks, while the others required an average of 6.1 weeks.
The average serum calcium rose slightly from 8.8 to 9.5 mg/dl during the 12 week study.
There were 13 episodes of hypercalcemia (Ca > 10.5 mg/dl) in 10 patients.
For the group, there were 4.7 episodes of hypercalcemia per 100 weeks of treatment compared to 0.53 episodes per week during the washout period.
The average serum phosphate levels were unchanged by 1α(OH)D2 therapy.
There were 30 episodes of hyperphosphatemia (P > 6.9 mg/dl) in 18 patients during treatment compared to 13 episodes in 6 patients during the washout; the rates of hyperphosphatemic episodes, 6.9/100 weeks during the washout versus 10.1/100 weeks during treatment, were not significantly different.
There was no alteration ofphosphate binders during the treatment phase.
A comparison of daily oral versus intermittent oral 1α(OH)D2 by Frazao et al revealed comparable efficacies of daily and thrice-weekly.
The incidences of hypercalcemia and hyperphosphatemia were very low in this small group of patients. A larger study was performed with 99 patients that consisted of an 8-week washout period, 16 weeks of open-label treatment with oral 1α(OH)D2 and 8 weeks of double-blind crossover to either placebo or continued 1α(OH)D2. Dosage was intiated at 10 µg 1α(OH)D2 3 times per week after each dialysis and adjusted to maintain PTH between 150 and 300 pg/ml while avoiding hypercalcemia or hyperphosphatemia.
PTH levels fell rapidly (35%) within 2 weeks and more slowly throughout the 16-week open-label treatment to a nadir of 44.7% of the baseline level.
The target PTH range was achieved in 82 of the 99 patients. Crossover to placebo resulted in a rapid rebound of PTH, while PTH levels remained suppressed in patients continued on 1α(OH)D2.
There were modest increases in serum calcium (+ 0.7 mg/dl) and phosphate (0.8 mg/dl) in the open-label period.
Hypercalcemia (Ca > 10.5 mg/dl) was detected in 15.3% of the measurements during the treatment period compared to 3.6% during the washout.
The prevalence of hyperphosphatemia (P > 6.9 mg/dl) was 18.9% and 6.6% in the treatment and washout periods, respectively.
Oral 1α(OH)D2 was judged to be safe and effective in treating secondary hyperparathyroidism and was approved for use in patients in the United States in 1999. Intravenous 1α(OH)D2 has also been introduced.
Maung et al entered patients from the intermittent oral study described above into a trial to compare the efficacy of intravenous 1α(OH)D2. Following an 8-week washout, patients were given placebo and 32 patients were treated with intravenous 1α(OH)D2 for 12 weeks.
The initial intravenous dose was 4 µg three times per week after dialysis, compared to the 10 µg dose of oral 1α(OH)D2 in the previous study, due to the 2.5 times higher bioavailabilityof the intravenous 1α(OH)D2.
PTH levels decreased progressively during 12 weeks of intravenous 1α(OH)D2 as it had with oral 1α(OH)D2.
Comparison of the PTH levels during the intravenous trial and the first 12 weeks of the oral trial revealed similar rates of decrease. Serum calcium and phosphate levels rose slightly with intravenous 1α(OH)D2 administration, but both the absolute and percent increases were lower than with oral 1α(OH)D2.
Incidents of hypercalcemia and hyperphsophatemia were also lower with intravenous 1α(OH)D2.
Thus, it appears that intravenous administration of 1α(OH)D2 may be safer than the oral formulation. Intravenous 1α(OH)D2 is now available for use in patients.
Falecalcitriol
Falecalcitriol is an analog in which the hydrogens on carbons 26 and 27 have been substituted with fluorine atoms.
This compound displays higher activity than 1,25(OH)2D3 in vivo due to its slower metabolism.
In an initial trial by Nishizawa et al, 43 renal failure patients were given daily oral falecalcitriol starting at a dose of 0.05 µg/d.
This dose was increased by 0.05 µg/d every two weeks, unless hypercalcemia (Ca > 10.5 mg/dl) was produced. At the end of the 12-week protocol, there was a mean reduction in intact PTH of 25%, with only a very small change in serum calcium (8.79 ± 0.12 to 9.09 ± 0.13 mg/dl).
More recently, Akiba et al compared the efficacy of falecalcitriol to alfacalcidol (1α(OH)D3) in a small group of renal failure patients with moderate to severe secondary hyperparathyroidism. The doses for falecalcitriol and alfacalcidol were 0.15-0.30 µg/d and 0.25-0.50 µg/d, respectively.
Both compounds were administered daily in oral form for 24 weeks.
Under these conditions, falecalcitriol was more effective than alfacalcidol in reducing PTH. While both increased serum calcium slightly at the doses used, the change was small and not significantly different for the two vitamin D analogs.
Further testing in larger groups of patients will be necessary to adequately evaluate the efficacy of falecalcitriol.
