1Shirasagi Hospital Kidney Center, 2Department of Nephrology and 3Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan
Correspondence and offprint requests to: Eiji Ishimura, MD, Department of Nephrology, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-mchi, Abeno-ku, Osaka 545-8585, Japan. Email: ish{at}med.osaka-cu.ac.jp
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Abstract |
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Methods. Parathyroid gland size was measured by ultrasonography in 25 patients with secondary hyperparathyroidism [serum intact parathyroid hormone (PTH) >300 pg/ml, 58.1 ± 2.8 years old, 15 males and 10 females], who were treated with maxacalcitol. Patients were divided into two groups according to the mean value of the maximum diameter of the glands: group S with a diameter <11.0 mm and group L with a diameter 11.0 mm. Between the two groups there were no significant differences in serum intact PTH, calcium or phosphate level or duration of haemodialysis.
Results. Mean (± SE) maximal diameter of detectable parathyroid glands was 11.0 ± 0.7 mm before treatment. At 424 weeks after administration of maxacalcitol, intact PTH concentrations decreased significantly in group S (from 546 ± 39 to 266 ± 34 pg/ml at 24 weeks; P < 0.01), but did not significantly change in group L (from 481 ± 39 to 403 ± 49 pg/ml at 24 weeks). At 24 weeks after maxacalcitol administration, the number of detectable parathyroid glands was significantly decreased in group S (from 2.2 ± 0.3 to 1.8 ± 0.4; P < 0.05), but not in group L. Serum calcium increased significantly in group L (from 9.6 ± 0.2 to 10.2 ± 0.3 mg/dl; P < 0.05), but not in group S. There was a significant correlation between reduction in PTH and parathyroid gland size (r = -0.42, P < 0.05).
Conclusions. These results indicate that the responsiveness to maxacalcitol therapy of secondary hyperparathyroidism is dependent on parathyroid gland size and that the simple measurement of maximum parathyroid gland diameter by ultrasonography may be useful for predicting responsiveness to maxacalcitol treatment.
Keywords: maxacalcitol; parathyroid hormone; secondary hyperparathyroidism; ultrasonography
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Introduction |
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Although increased parathyroid gland size has been reported to predict PTH-lowering by calcitriol [8,11], consistent findings regarding the effect of parathyroid gland size on responsiveness to vitamin D therapy have not been obtained, partly because only a few studies have been conducted on this [810]. In the present study, we examined a possible relationship between parathyroid gland size and responsiveness to long-term maxacalcitol treatment in order to elucidate the clinical usefulness of measuring parathyroid gland size by ultrasonography before treatment.
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Subjects and methods |
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Administration of maxacalcitol and measurement of serum parameters
Five µg maxacalcitol was administered intravenously at the end of each dialysis session. Before the start of maxacalcitol some patients received small oral doses of intermittent or daily calcitriol or alfacalcidol (see Results) and the patients were converted from intermittent or daily calcitriol or alfacalcidol to intravenous maxacalcitol, according to the advice from the Ethics Committee of the hospital. Doses of maxacalcitol were increased from 5 to 10 µg when intact PTH was >500 pg/ml after 1 month. When serum calcium concentration was >11.5 mg/dl and/or calciumphosphate product was >70, maxacalcitol was temporarily discontinued. Maxacalcitol administration (5 µg) was resumed when the condition disappeared. When PTH levels were decreased below 150 pg/ml, maxacalcitol was temporarily discontinued. Maxacalcitol administration (5 µg) was resumed when PTH increased again to >150 pg/ml.
In all patients, serum calcium and phosphate concentrations were measured twice a month and intact PTH once a month. Serum calcium was corrected with serum albumin as follows (in this case serum albumin was <4.0 g/dl):
corrected calcium = measured calcium concentration
+ (4 - measured albumin concentration)
where the units for measured calcium concentration and measured albumin concentration are mg/dl and g/dl, respectively.
Ultrasonography of parathyroid glands
Ultrasonography was performed within 1 month before administration of maxacalcitol and at 24 weeks after initiation of maxacalcitol administration, by a single examiner (H.C.) who was blind to clinical data. Using an 8 MHz ultrasonography probe (SSA-350A; Toshiba, Japan), a gland as small as 2.0 mm in maximum diameter can be detected in our hospital. The coefficient of variance of parathyroid gland measurement by the examiner (H.C.) was 2.7%.
Statistical analysis
Data are presented as means ± SE. Unpaired Students t-test was used for comparison between the two groups and paired Students t-test for comparison between the baseline and follow-up data after maxacalcitol administration. Correlation and linear regression analyses were performed to examine the relationship between the responsiveness to maxacalcitol and clinical parameters. Findings of P < 0.05 were considered significant. All analyses were performed using statistical software (StatView 5; SAS Institute Inc., Cary, NC, USA) designed for the Macintosh computer.
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Results |
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Parathyroid glands detected by ultrasonography
Before the start of maxacalcitol, one to four parathyroid glands were detected in all the patients, the smallest gland being 3.0 mm in maximum diameter. The mean maximum parathyroid gland diameter detected by ultrasonography in 25 patients was 11.0 ± 0.7 mm. In the analysis, these 25 patients were divided into two groups according to the mean value of maximum diameter of the parathyroid gland: group S (n = 14) with maximum diameter less than the mean value (11.0 mm) and group L (n = 11) with maximum diameter equal to or greater than the mean value. The age, duration of haemodialysis and clinical parameters related to parathyroid function of the patients of groups S and L are summarized in Table 1. Vitamin D dosages (µg/week) during the 3 month period preceding maxacalcitol therapy were calculated, with estimation of calcitriol dosage. During the 3 months period prior to maxacalcitol initiation, 16 patients (nine in group S and seven in group L) received intermittent oral administration of alfacalcidol or calcitriol (0.1251.5 µg calcitriol, mostly 23 times a week), five patients (three in group S and two in group L) received it daily (0.1250.5 µg calcitriol) and four patients (two each in groups S and L) received no vitamin D. The dosage of vitamin D (mean ± SE) was 2.0 ± 0.3 µg/week in group L and 1.4 ± 0.4 µg/week in group S, as the dose of calcitriol. There was no significant difference in vitamin D dosage prior to maxacalcitol initiation between groups S and L (P = 0.250). Intact PTH, corrected calcium, phosphate and alkaline phosphatase did not differ significantly between the two groups. The maximum diameter in group S was 8.5 ± 0.6 mm and that in group L was 14.2 ± 0.7 mm. The number of detectable parathyroid glands in group L was significantly larger than that in group S (3.2 ± 0.2 vs 2.2 ± 0.3; P < 0.05). There was no significant correlation between parathyroid gland size and intact PTH level before treatment and none between parathyroid gland size and serum calcium or phosphate level before treatment.
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Changes in calcium and phosphate
Serum calcium level (corrected calcium value) was not significantly changed after maxacalcitol administration in group S, whereas serum calcium in group L significantly increased after maxacalcitol administration (P < 0.05, paired Students t-test). Serum calcium concentrations in group L were significantly higher than those in group S at 4, 8, 12 and 24 weeks after initiation of maxacalcitol administration (Figure 3). Serum calcium at 4 weeks, when the highest calcium values were observed, was significantly positively correlated with both parathyroid gland size (r = 0.54, P < 0.01) and baseline calcium level (r = 0.61, P < 0.01), but not with baseline serum phosphate or intact PTH level. Serum phosphate concentrations were not significantly changed during the 24 weeks following initiation of maxacalcitol administration in group S, while they tended to increase in group L. Although baseline calciumphosphate product did not differ significantly between the two groups (51.7 ± 13.5 vs 56.1 ± 12.1 in groups S and L, respectively; P = 0.354), at 24 weeks it was significantly higher in group L than in group S (50.2 ± 16.5 vs 65.2 ± 14.9 in groups S and L, respectively; P < 0.05).
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Discussion |
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Maxacalcitol is a recently developed vitamin D analogue, which has been found to exhibit less calcaemic activity in animal studies [5]. It has been proven to be effective in the treatment of secondary hyperparathyroidism [4,6,7]. However, it has been reported to be ineffective in some patients [7], as has also been observed with calcitriol pulse therapy [6,7]. Tsukamoto et al. [7] recently reported that serum calcium levels at the start of treatment in patients who responded well to maxacalcitol (n = 5) were significantly lower than those in patients who did not respond well to it (9.1 ± 0.3 vs 10.3 ± 0.3 mg/dl). Malberti et al. [9] also reported that the serum ionized calcium level of the patients who were responsive to calcitriol therapy was significantly lower than that of those who were not responsive (ionized calcium: 5.0 ± 0.2 vs 5.3 ± 0.2 mg/dl). In the present study, however, baseline serum calcium in group S was also slightly lower than that in group L, although not to a statistically significant extent (9.3 ± 0.2 vs 9.6 ± 0.2 mg/dl; P = 0.09). On linear regression analysis, however, we found a significant relationship between average per cent reduction of PTH and baseline serum calcium level. This finding suggests that baseline serum calcium level also predicts responsiveness to maxacalcitol.
In the present study, after maxacalcitol treatment, serum calcium level was significantly increased in group L, in which maxacalcitol did not significantly suppress PTH levels. This suggests that the parathyroid glands of group L patients may have been very close to being maximally suppressed by higher levels of serum calcium. Serum calcium at 4 weeks, when the highest mean calcium level was observed, was positively correlated with parathyroid gland size. Malberti et al. [9] also reported that serum ionized calcium levels after calcitriol therapy in patients who were non-responsive to calcitriol therapy were significantly higher than in those who were responsive to it. Our results are consistent with their findings. Furthermore, in nine excluded patients for whom maxacalcitol therapy was discontinued due to increase in serum calcium >11.5 mg/dl at two measurements in 1 month between 4 and 16 weeks, baseline maximal parathyroid gland diameter was 14.9 ± 2.8 mm, showing that the level of serum calcium in patients with larger parathyroid glands was readily increased by maxacalcitol. The study performed by Kurz et al. [12] demonstrated that the PTH level of histologically proven low turnover bone disease was 116 ± 30 pg/ml (maximum: 390 pg/ml) and the study by Qi et al. [13] demonstrated that the specificity of serum intact PTH >450 pg/ml for prediction of high bone turnover is 100% for haemodialysis patients. These two studies suggest that most of our patients with higher PTH levels (481 ± 39 pg/ml) in group L may have had high bone turnover. The significant increases in serum calcium and phosphate levels also seen in group L may reflect a more advanced stage of secondary hyperparathyroidism and may have been caused not only by increased bone absorption induced by high PTH levels (high bone turnover), but also by increased intestinal absorption of calcium and phosphate induced by maxacalcitol. The increase in serum calcium levels after maxacalcitol therapy, however, may have been induced by adynamic bone disease or low bone turnover due to prior vitamin D therapy and maxacalcitol initiation in our patients. Goodman et al. [14] reported that bone formation decreased in some patients despite persistently high serum PTH levels after intermittent calcitriol therapy in peritoneal dialysis patients. In their study, PTH levels of adynamic bone after calcitriol pulse therapy were reported to be usually <150 pg/ml. In the present study, prior vitamin D treatment and initiation of maxacalcitol may have caused bone formation to fall and led to a tendency towards low bone turnover from high bone turnover. This tendency may have caused a decreased pool size for calcium added to extracellular fluid, thus, possibly leading to hypercalcaemia in group L following intestinal calcium absorption enhanced by maxacalcitol. Low bone turnover favouring hypercalcaemia, in spite of high PTH levels in the present study, may therefore have been present in at least some patients, particularly when considering the prompt increase in serum calcium after maxacalcitol therapy. Further studies with bone biopsies must be performed to examine the issue of the possible induction of low bone turnover despite persisting high PTH levels and hypercalcaemia after active vitamin D treatment.
A higher serum phosphate has been reported to be a predictor of poor responsiveness to calcitriol therapy in patients with secondary hyperparathyroidism as well [10,15], although this was not observed by others [9]. In the present study, although baseline serum phosphate levels did not differ significantly between groups S and L, a borderline significant (P = 0.08) relationship between baseline serum phosphate level and average per cent PTH reduction after maxacalcitol treatment was observed and phosphate levels tended to increase in group L. Since hyperphosphataemia is an important contributor to hyperparathyroidism [16], our results also suggest the importance of phosphate control in vitamin D treatment in patients with secondary hyperparathyroidism.
Some studies have examined the relationship between responsiveness to vitamin D and parathyroid gland size in patients with secondary hyperparathyroidism [2,811]. Fukagawa et al. [2,8] reported that, in their experience, patients with at least one gland larger than 0.5 cm3 or 1 cm in diameter were usually refractory to calcitriol pulse therapy. Katoh et al. [11] recently reported that the suppressive effect of a single oral dose of 8 µg calcitriol on PTH was reduced in patients with enlargement of parathyroid glands detectable by ultrasonography. Malberti et al. [9] examined 35 patients with secondary hyperparathyroidism and found response heterogeneity to calcitriol. They also found that parathyroid gland volume was a significant predictor of responsiveness [9]. Quarles et al. [10] also found response heterogeneity to calcitriol, but parathyroid gland volume was not predictive of calcitriol response. In the present study, we examined effect of maxacalcitol on reduction of PTH level. We demonstrated that patients with larger parathyroid glands with maximum diameter 11.0 mm did not significantly respond to maxacalcitol treatment, whereas those with maximum diameter <11.0 mm significantly responded to treatment. This finding is similar to the experience of Fukagawa et al. [8], although a statistical analysis was not performed to elucidate parathyroid gland size as a limitation of calcitriol therapy. On linear regression analysis, we found a significant relationship between parathyroid gland size and per cent reduction of intact PTH after maxacalcitol. Our findings are consistent with those of Malberti et al. [9], but not with those of Quarles et al. [10]. These discrepant findings may be due to the fact that Quarles et al. treated patients with more advanced hyperparathyroidism, higher PTH levels (mean: 920 pg/ml) and larger parathyroid volume (mean: 2.0 cm3). Indeed, the parathyroid gland volume in calcitriol responders in the study by Malberti et al. was 0.4 ± 0.3 cm3 and significantly smaller than that of non-responders (2.4 ± 2.1 cm3). If the parathyroid glands are assumed to be spherical in the patients of our study, the parathyroid volume of group S can be calculated (
r3 / 6) to be 0.32 ± 0.1 cm3 and that of group L 1.50 ± 0.7 cm3.
Taken together, the results of the present study and of previous studies by others suggest that limitation of suppression of PTH levels by vitamin D therapy depends on parathyroid gland size and that the limitation is parathyroid glands 11 mm in maximum diameter, even when vitamin D analogues are used. It appears that larger parathyroid glands are refractory to calcitriol therapy and also exhibit poor suppression of PTH secretion in the presence of calcium increase [17]. We further found that, after maxacalcitol treatment, the number of detectable parathyroid glands significantly decreased in group S, although the decrease in number was not significant in group L. Maximum parathyroid gland diameter before treatment was significantly larger than gland diameter at 24 weeks in group S, although in group L the diameter before treatment was not significantly different from that at 24 weeks. Serial ultrasonography performed by Fukagawa et al. [8] also demonstrated decrease in parathyroid gland size in some cases after calcitriol treatment. In our previous study, a rapidly growing, large parathyroid gland had significantly less vitamin D receptor content (32.6 ± 9.6 fmol/mg protein) than a non-growing, small parathyroid gland in the same patient (111.8 ± 0.8 fmol/mg protein) [18]. The former had nodular hyperplasia and the latter diffuse hyperplasia. Since calcitriol is reported to induce apoptosis in parathyroid cells of secondary hyperparathyroidism in vitro [19], the ultrasonographically visible reduction in the number and size of parathyroid glands in the present study may have been induced by apoptosis in group S, in which parathyroid glands may have had diffuse hyperplasia and higher content of vitamin D receptor, while apoptosis was not markedly induced in group L whose parathyroid gland may have had nodular hyperplasia and lower content of vitamin D receptors. Parathyroid glands of size >0.5 cm3 usually appear to present nodular hyperplasia [20]. The nuclei of hyperplastic parathyroid cells have a lower vitamin D receptor expression [18,21], leading to refractoriness to vitamin D therapy.
In summary, responsiveness to maxacalcitol therapy of secondary hyperparathyroidism is dependent on parathyroid gland size. A simple measurement of the maximum diameter of parathyroid glands by ultrasonography can be useful for predicting responsiveness to treatment. When a poor reduction in serum intact PTH and an increase in serum calcium are observed after vitamin D treatment in patients with large parathyroid glands, parathyroidectomy and/or percutaneous ethanol injection treatment [22] should be considered without delay. We propose, based on the findings of the present study, that parathyroid glands with a maximal diameter >11.0 mm do not respond well to maxacalcitol therapy.
Conflict of interest statement. None declared.
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References |
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