| Abstract|| |
Patients with end-stage renal failure (ESRF) on maintenance dialysis, commonly develop secondary hyperparathyroidism and renal osteodystrophy (ROD). Alfacalcidol, taken orally or administered intravenously, is known to reverse these complications. In this study, 19 ESRF patients, who were on dialysis (13 on hemodialysis and six on peritoneal dialysis) for longer than six months and having serum parathormone levels at least four times normal and serum calcium less than 2.1 mmol/L, were randomly allocated to treatment with oral or intravenous (i.v.) alfacalcidol for a period of 12 months. There were six patients on hemodialysis (HD) and three on peritoneal dialysis (PD) in the oral treatment group while in the i.v. group there were seven patients on HD and three on PD. Clinical and serial biochemical assessments showed no statistically significant difference between the orally- and i.v.-treated patients in terms of suppressing secondary hyperparathyroidism and osteodystrophy. However, patients with features of mild ROD on bone histology, had more satisfactory changes in biochemistry when compared to others. Our results further support the use of intermittent oral alfacalcidol in ESRF patients because of its cost effectiveness, ease of administration and convenience, especially for peritoneal dialysis patients.
Keywords: End-stage renal failure, Osteodystrophy, Hyperparathyroidism, Alfacalcidol, Dialysis.
|How to cite this article:|
Mitwalli AH, Alam AA. Intermittent Oral Versus Intravenous Alfacalcidol in Dialysis Patients. Saudi J Kidney Dis Transpl 2000;11:174-80
|How to cite this URL:|
Mitwalli AH, Alam AA. Intermittent Oral Versus Intravenous Alfacalcidol in Dialysis Patients. Saudi J Kidney Dis Transpl [serial online] 2000 [cited 2020 Sep 27];11:174-80. Available from: http://www.sjkdt.org/text.asp?2000/11/2/174/36674
| Introduction|| |
Secondary hyperparathyroidism and renal osteodystrophy (ROD) are major complications of chronic renal failure., The need for parathyroidectomy in such patients has steadily decreased because of good control of serum phosphorous levels as well as the use of vitamin D analogues,  which could be administered orally or intravenously. ,,,,,,,,,,,,, Studies comparing the two routes of administration have not found any superiority of the intravenous (i.v.) route over the oral.  A study on the use of oral alfacalcidol (1 hydroxy cholecalciferol) in a dose of 0.5 µgm daily for a period of six months showed no apparent effect on the level of circulating parathyroid hormone (PTH) despite the fact that the serum calcium (S. Ca) level was in the upper limit of normal. This was ascribed to the first pass metabolism of the orally administered vitamin.  It was subsequently shown that high doses of calcitriol (i.v. or oral) given as pulses twice or thrice weekly, could effectively suppress PTH levels. , Recent studies on intermittent oral calcitriol therapy suggest that it is an effective route of administration and that it may cause less hypercalcemia than daily oral therapy. , Alfacalcidol is more commonly used in Europe, Canada and Japan whereas calcitriol is preferred in the USA. Alfacalcidol when used orally for preuremic, and i.v. for uremic patients has been shown to decrease bone turn over effectively.  Researchers in New Zealand have shown that both oral and i.v. alfacalcidol were equally effective in suppressing PTH secretion.  In a study from Poland, oral alfacalcidol was found to be as effective as oral calcitriol in suppressing PTH levels in patients with severe secondary hyperparathyroidism. 
The aim of our study was to compare the efficacy of oral and i.v. alfacalcidol administration on ROD in two groups of patients with end-stage renal failure (ESRF) on maintenance dialysis, with emphasis on the associated biochemical and bone changes.
| Patients and Methods|| |
Nineteen ESRF patients on maintenance dialysis at the Security Forces Hospital, Riyadh, Saudi Arabia between January 1, 1991 and December 31, 1994 were enrolled into the study. There were 10 males (52.6%) and nine females (47.4%). Their ages ranged between 15 and 54 years with a mean of 37.3 ± 14.5 years. The mean age of males was 36.0 ± 15.4 years and that of the female patients was 38.7 ± 13.5 years (P > 0.05). Thirteen patients (10 males and 3 females) were on hemodialysis (HD) for four hours, thrice weekly. They had been on HD for a mean duration of 64.5 ± 1.4 months (range = 50 - 105 months). Six patients, all female, were on intermittent peritoneal dialysis (PD), 2-liter, hourly cycles for 24 hours per session, twice weekly. They had been on PD for a mean duration of 77.2 ± 25.6 months (range = 52128 months). The etiology of ESRF among the study patients was diabetic nephropathy (n=5), glomerulonephritis (n=4), interstitial nephritis (n=3), hypertension (n=2), and unknown (n=5).
The inclusion criteria for the study patients were: age less than 60 years, duration on dialysis (HD or PD) more than six months, serum PTH levels elevated to at least four times the normal and S. Ca levels of less than 2.1 mmol/L. Exclusion criteria included: history of sensitivity to alfacalcidol, persistent hypercalcemia (S. Ca > 2.8 mmol/L), calcium-phosphorus product > 6, evidence of aluminum toxicity (serum Al > 50 μmol/L), previous bone histology suggestive of adynamic (aplastic) bone, long-term therapy with anticonvulsant medications or corticosteroids and/or previous parathyroidectomy.
The patients were randomly divided into two groups using random tables. The first group included nine patients (6 HD and 3 PD) who received oral alfacalcidol. The second group of ten patients (7 HD and 3 PD) received i.v. alfacalcidol. For the first two weeks all patients received 1 µgm alfacalcidol three times per week. Subsequently, the dose was increased to 2 µgms thrice weekly for two weeks and later to 3 µgms thrice weekly for four weeks. Eventually, the dose was adjusted to maintain the S. Ca level around 2.6 mmol/L and PTH. Patients were maintained on that dose for a total period of 12 months. The patients on HD received alfacalcidol after a dialysis session and the therapy was supervised by the dialysis staff to ensure compliance.
The diet and dialysis schedules were kept constant in all patients. The kt/v was aimed at > 1.2 in both groups. Dialysate calcium concentration was 1.75 mmol/L in both hemo- and peritoneal dialysis solutions. When hypercalcemia (S. Ca > 2.8 mmol/L) occurred, treatment with vitamin D was with held until the Se Ca level returned to normal range. Depending on the severity of hypercalcemia, the dose of alfacalcidol was subsequently adjusted between 0.5-3.0 µgm. None of the study patients were on aluminum-containing drugs. Follow-up involved detailed clinical assessment and weekly determination of S. Ca, phosphorus, albumin, bicarbonate and alkaline phosphatase levels. The PTH and aluminum levels were checked monthly and 3-monthly respectively by radioimmunoassay. All patients had skeletal surveys, dual photon study for bone mineral density and bone biopsy, which was performed once at the beginning of the study and again after 12 months of treatment.
Tetracycline labeling was done by the following protocol. Tetracycline hydrochloride, 250 mg twice daily, was administered for two days. The drug was discontinued and administered 10 days later for four days. Trans-iliac trephine bone biopsies were performed from the posterior iliac spine four days after the last dose of tetracycline. The bone samples were processed as previously described.  The histomorphometric methods were in compliance with the nomenclature according to the ASMBR histomorphometry nomenclature committee.  Biopsies were evaluated by a competent histopathologist in England (JSPS: Bewley House 32, Jamestown Road, London NW17BY, UK). Data compilation was done without knowledge of the route of administration of alfacalcidol.
Student's 't' test, chi-square test and analysis of variance (ANOVA) were used to evaluate the statistical significance between the oral and i.v. groups. Probability values less than 0.05 were considered statistically significant.
| Results|| |
The mean, pre- and post-treatment values of PTH, Se Ca and phosphorus of both study groups showed statistically significant improvement after starting alfacalcidol [Table - 1]. The improvement was similar and no difference was observed when the two groups were compared using ANOVA. Also, regardless of the route of administration of alfacalcidol, the changes in the mean values of PTH and S. Ca were statistically significant in both HD and PD patients [Table - 2]. Patients on PD, as a group, had higher mean PTH levels when compared with patients on HD. There was a significant decrease in the mean serum phosphorus in the HD group, which was not seen in the PD group. There was however, no significant change in the alkaline phosphatase levels in either group. Also, the changes in mean alkaline phosphatase levels were not significantly different in patients on either HD or PD.
Bone biopsies revealed four different histological changes and were grouped as follows: mild ROD changes (n = 7), secondary hyperparathyroidism features (n = 6), mixture of these two changes (n = 4) and osteomalacia (n = 2). None of the patients had adynamic bone disease. Baseline histological changes according to the route of administration of alfacalcidol were as follows: i.v. group; mild ROD (n = 4), secondary hyperparathyroidism (n = 3), mixed disease (n = 3) and osteomalacia none. Oral group; mild ROD (n = 2), secondary hyperparathyroidism (n = 1), mixed disease (n = 4) and osteomalacia (n = 2). The histological types at baseline were not statistically different among the two groups. Repeat bone biopsies at the end of 12 months of therapy revealed restoration to normal bone histology particularly in patients with mild ROD and significant improvement in changes of secondary hyperparathyroidism, irrespective of the route of administration. Mean serum aluminum levels were < 50 pmol/L and bone biopsies were all negative for aluminum staining.
A comparison of the mean pre- and posttreatment values of PTH, S. Ca, alkaline phosphatase and phosphorus according to the histological types is given in [Table 3]. Patients with mild ROD changes showed statistically significant improvement in all the biochemical parameters except for alkaline phosphatase levels. Patients with osteomalacia did not show significant changes in any of the four laboratory tests. Skeletal survey did not show significant changes before and after treatment and the dual photon study showed significant improvement of bone density in both treatment groups.
| Discussion|| |
Several studies have shown that alfacalcidol is effective in suppressing PTH levels and causing improvement in changes of secondary hyperparathyroidism as seen on bone histomorphometry. ,,,, Alfa calcidol, used as pulse therapy by oral or i.v. routes, has also been shown to be effective in suppressing secondary hyperparathyroidism. ,,,, In our study, both the oral and i.v. alfacalcidol groups showed similar reduction of PTH levels at the end of 12 months. Also, when assessed separately, both the HD and PD groups showed significant reduction of PTH levels. Bone histology also improved at the end of therapy.
Hypercalcemia and hyperphosphatemia are known to complicate therapy with vitamin D derivatives. , Mild increase in S. Ca has been reported with alfacalcidol therapy concomitant with suppression of PTH levels.  Ljunghall et al have reported hypercalcemia occurring in a majority of their patients and they also noted an increase in PTH levels when the dose of alfacalcidol was reduced to counter hypercalcemia.  Significant hypercalcemia is reportedly less frequent with the use of low dialysate calcium, intermittent dosing and careful dose adjustments.  In our study, the mean S. Ca level increased in both oral and i.v. groups. However, true hypercalcemia (> 2.8 mmol/L) was encountered in 36.7% of our patients, three from the i.v. group, and four from the orally treated group. The S. Ca levels were managed by discontinuing therapy for a period of two to four weeks.
Hyperphosphatemia was not a significant occurrence in our patients due to use of phosphate binders and also suggests that our study patients were compliant with use of these drugs. We noticed high alkaline phosphate levels mainly in the i.v. group, most of whom also had significantly higher PTH levels at the beginning of the study. Although significant improvement in PTH levels was noted in this group, the PTH levels continued to be relatively higher in these patients at last follow up, resulting in higher alkaline phosphatase levels. Davison et al have reported that metastatic calcification can be avoided with effective suppression of phosphate levels along with alfacalcidol therapy.  It is therefore important to keep serum phosphorus levels below 1.6 mmol/L (5 mg/dl) by strict dietary restriction and use of phosphorus binders.
Dual photon bone densitometry performed before and at the end of treatment indicated the baseline severity of bone disease as well as improvement noted in bone density after 12 months, associated with histological improvement. Similar findings have been reported by other authors. 
Although our study was conducted on a small number of patients, we could demonstrate definite improvement in bone histomorphometry. Our patients could not be randomized successfully to oral or i.v. groups according to baseline PTH. This was due to the fact that patients on PD had relatively higher PTH levels and thus, two patients with PTH >2000 pg/ml were included in the i.v. group. Although this increased the mean baseline level of PTH in this group, the patients still showed a significant improvement at completion of the study.
In conclusion, both oral and i.v. alfacalcidol, administered intermittently, were able to equally suppress secondary hyperparathyroidism in dialysis patients. This was shown by improvement in PTH levels as well as improvement in bone histomorphometry and bone density.
Hypercalcemia was not very common and could be managed easily by temporarily discontinuing therapy.
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Ahmed H Mitwalli
Department of Medicine, King Khalid University Hospital, P.O. Box 2925, Riyadh 11461
[Table - 1], [Table - 2]