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Treatment of hypocalcemia caused by hypoparathyroidism or pseudohypoparathyroidism with domestic-made calcitriol: a prospective and self-controlled clinical trial

WANG, Ou; XING, Xiao-ping; MENG, Xun-wu; XIA, Wei-bo; LI, Mei; JIANG, Yan; HU, Ying-ying; LIU, Huai-cheng

Editor(s): LIU, Dong-yun; JI, Yuan-yuan

Author Information
doi: 10.3760/cma.j.issn.0366-6999.2009.03.008
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Abstract

The principal function of parathyroid hormone (PTH) is to maintain the serum calcium level within a narrow physiological range. Insufficient production of PTH by the parathyroid glands (hypoparathyroidism) or a resistance against its action on target organs (pseudo-hypoparathyroidism) may cause parathyroid-related hypocalcemia associated with hyperphosphatemia. The typical clinical manifestations include cramps, convulsion, extremity paresthesia, calcification of basal ganglia, cataracts, etc.1–3 Hypoparathyroidism and pseudo-hypoparathyroidism are rare. An epidemiologic survey conducted in Japan showed the prevalence rate of hypoparathyroidism and pseudohypoparathyroidism as (5.5–8.8)/million and (2.6–4.2)/million, respectively.4

A Lifelong treatment of calcium combined with vitamin D or its metabolites is always necessary for these patients. Calcitriol (1,25(OH)2D3) is one of the active forms of vitamin D analogues and also plays an important role in maintenance of calcium homeostasis. It has been successfully used in treatment of hypoparathyroid and pseudohypoparathyroid patients since its discovery. Compared with the prodrugs such as cholecalciferol and tachysterol, calcitriol has shorter half-life and more predictable bioavailability, which decrease the risk of vitamin D over- and underdosage and make it safer and more effective in treatment of such patients, even during pregnancy. However, due to the rarity of such diseases, clinical intervention trials, especially prospective studies, are still lacking. Most of the knowledge of treatment of hypoparathyroidism or pseudohypoparathyroidism is based on a few retrospective studies, case reports, or clinical observations of very small-sample-size subjects.5–10 To provide more potent evidence for the clinical practice in hypoparathyroidism and pseudo-hypoparathyroidism, here we designed a prospective, self-controlled trial to observe the efficacy and safety of domestic-made calcitriol (1,25(OH)2D3) in treatment of hypothyroidism and pseudohypoparathyroidism.

METHODS

Subjects

This study was performed in the outpatient department of endocrinology in Peking Union Medical College Hospital. From January 2005 to March 2006, twenty-two hypoparathyroid and 2 pseudohypoparathyroid patients aged (36.5±11.0) years were studied (male/female: 9/16). The course of hypoparathyroidism was (8.2±8.2) years. Among them, 16 cases were diagnosed as idiopathic hypothyroidism, 2 cases as pseudohypoparathyroidism and 6 cases as postsurgical hypoparathyroidism.

The inclusion criteria included: (1) hypocalcemia, serum calcium (Ca) levels ≤1.88 mmol/L or plasma ionized calcium (iCa) levels ≤0.96 mmol/L; (2) normal liver and kidney function; (3) serum alkaline phosphatase (ALP) levels were normal in idiopathic hypoparathyroidism patients; (4) hyperphosphatemia, serum phosphorus (P) levels ≥1.49 mmol/L in adults and ≥1.94 mmol/L in children; (5) serum PTH levels were lower than normal or in inappropriate normal range which could not be excited by hypocalcemia in idiopathic and postoperative hypoparathyroidism participants, serum ALP and PTH levels increased in pseudohypoparathyroid patients; (6) hypocalcemic cataracts; (7) calcification of basal ganglia proved by CT scanning. Patients with (1) + (2) and at least 2 criteria of (3) to (7) were enrolled in this study.

Patients with non-functional digestive or neuropsychiatric diseases, other severe chronic diseases which needed long-term therapy, impaired liver function, allergic to study drugs, or taking other drugs which might affect Ca level would be excluded. Patients with severe side effects or complicated with other diseases during treatment and unable to insist on the treatment would be withdrawn.

The clinical trial was approved by the local ethical committee of Peking Union Medical College Hospital. Informed consent was obtained from all subjects.

Treatment protocol

History recording, physical examination and biochemical markers measurements were completed in the enrolled patients. At baseline, the biochemical markers included liver and kidney function, blood routine test, urine routine test, serum and 24-hour collection of urinary Ca and P, plasma iCa, serum ALP, and serum PTH.

All patients were followed every 4 weeks of the 12-week study. Hypocalcemic symptoms (including extremity parasthesia, cramps and muscular weakness) and signs (including Chvostek's sign and Trousseau's sign) were recorded. Blood Ca, P, iCa and 24-hour collection of urinary Ca were monitored to adjust the dose of calcitriol. Side effects were also reported.

Oral calcitriol (Haier Pharmaceutical Co. LTD, China, 0.25 μg/capsule) was administered at an initial dose of 0.5–1.0 μg divided to twice or three times daily according to the severity of hypocalcemia. The dose of calcitriol was adjusted to achieve a Ca level within or just below the normal range (2.00–2.25 mmol/L) and elimination of hypocalcemic symptoms and signs. All patients received calcium carbonate three times daily containing elemental calcium of 1.2 g/d.

Effect evaluation

It was graded as effective, partly effective and non-effective. Effective: symptoms and signs of hypocalcemia disappeared with serum Ca ≥2.00 mmol/L or plasma iCa ≥1.00 mmol/L, and the improvement of hyperphosphatemia (serum P ≤1.62 mmol/L or lowering magnitude ≥0.81 mmol/L). Partly effective: symptoms and signs of hypocalcemia alleviated significantly with serum Ca 1.88–1.98 mmol/L and/or the rising magnitude of iCa ≥0.38 mmol/L. Non-effective: the above-mentioned standards couldn't be satisfied.

Biochemical markers measurements

All biochemical markers were measured by multi-channel autoanalyzer at Peking Union Medical College Hospital central laboratory except for PTH and iCa determined at laboratory of department of endocrinology. Serum PTH level (normal range 7–53 pg/ml) was measured by chemiluminescent immunometric assay (Diagnostic Products Corperation, Los Angeles, CA, USA). The intra-assay coefficient of variation (CV) was 5.0% and inter-assay CV was 5.4%. Plasma iCa level (normal range (1.18±0.05) mmol/L) was measured by ISE Ca2+/pH analyzer (Bayer, German). The intra-assay and inter-assay CV were 0 (n=5) and 3.3% (n=76), respectively.

Statistical analysis

SPSS 11.5 software was used to analyze the effect of treatment. Quantitative data were presented as mean ± standard deviation (SD) and assessed by self-paired t test. Qualitative data were assessed by chi-square test. Two-sided P <0.05 was considered statistically significant.

RESULTS

Baseline characteristics

In 24 patients with hypoparathyroidism before treatment, there were 21, 19, and 13 patients suffering from extremity paresthesia, cramps and muscular weakness, respectively. Ten patients had a history of seizure. Four patients complained memory impairment. Eight of 9 patients taking ophthalmological examinations were detected with cataracts. Thirteen of 16 patients taking CT were detected with calcification of basal ganglia. Chvostek's sign and Trousseau's sign were positive in 18 and 23 patients, respectively. Liver and kidney function were normal in all of the patients. Serum PTH levels were <1.0–2.9 pg/ml in idiopathic hypoparathyroidism subjects, 501 pg/ml and 552 pg/ml in 2 pseudohypoparathyroidism patients respectively, and <1.0–6.5 pg/ml in patients secondary to cervical surgery. Blood Ca, iCa and P levels were (1.54±0.25) mmol/L, (0.64±0.10) mmol/L and (2.00±0.46) mmol/L, respectively. Serum ALP levels were (78.7±25.4) U/L except for the two pseudohypoparathyroidism patients whose ALP were 333 U/L and 162 U/L respectively. The 24-hour collection of urinary Ca and P were (2.24±2.02) mmol and (13.16±7.72) mmol, respectively.

Changes in symptoms and signs

Twenty patients were included by the end of this study. At the end of treatment, muscular weakness, cramps, extremity paresthesia, Chovestek's sign and Trousseau's sign relieved in 76.9%, 100%, 94.4%, 93.3% and 78.9% of patients, respectively (Table 1).

Table 1
Table 1:
Changes in symptoms and signs before and after treatment with calcitriol (n)

Changes in biochemical markers

Table 2 showed the blood Ca, iCa, P and urinary Ca levels before treatment and 4 weeks, 8 weeks, and 12 weeks after treatment. Serum Ca levels increased significantly and P levels decreased significantly even at the 4th week of treatment. Among them, 14 patients were followed at the 2nd week, when their serum Ca levels increased significantly ((1.88±0.24) mmol/L vs (1.54±0.25) mmol/L, P <0.001) and serum P levels decreased significantly ((1.71±0.28) mmol/L vs (2.00±0.46) mmol/L, P <0.001) than baseline. In the 20 patients who were included by the end of this study, serum Ca increased by (0.71±0.36) mmol/L and serum P decreased by (0.44±0.32) mmol/L at the 12th week, of which, 11, 6 and 3 patients had serum Ca levels ranged ≥2.20 mmol/L, 2.13–2.20 mmol/L and 2.00–2.13 mmol/L, respectively. Serum P levels became normal in 8 patients. Three, four and eight patients had hypercalciuria at the 4th, 8th and 12th week of treatment, respectively, which were reduced by thiazide diuretics.

Table 2
Table 2:
Changes in biochemical markers before and after treatment with calcitriol (mean±SD (n))

Dose of calcitriol

The final dose of calcitriol was (1.09±0.50) μg/d (range 0.50–2.25 μg/d), divided to twice or three times daily.

Effect evaluation

It was graded as effective, partly effective and non-effective as aforementioned. In the 20 patients, 16 (80%) and 4 (20%) patients were assessed as effective and partly effective, respectively. The effective rate reached 100%. Even in 4 dropped-out patients, serum Ca level increased to normal or nearly normal range at the 4th week and symptoms extenuated or relieved at the 4th or 8th week (data not shown).

Safety and compliance

One patient complained of thirsty and dry cough while taking calcitriol of 1 μg/d (serum Ca 2.20 mmol/L), which relieved when the dose was reduced to 0.875 μg/d (serum Ca 2.33 mmol/L). There were 3, 4 and 8 patients developing hypercalciuria (24-hour urinary Ca >8.75 mmol) at the 4th, 8th and 12th week of treatment (serum Ca 1.80–2.20 mmol/L), respectively, which were reduced by hydrochlorothiazide with a dose of 25 mg/d. One patient had hypercalcemia (serum Ca 2.87 mmol/L) at the 12th week, which relieved (serum Ca 2.15 mmol/L) 2 weeks after adjustment of calcitriol dose from 1 μg/d to 0.75 μg/d.

Blood pressure and heart rate were normal throughout the treatment period. No gastrointestinal symptoms or rashes were reported.

Four patients dropped out for inconvenience of follow-up at the 4th (n=3) and 8th week (n=1).

DISCUSSION

In this study, domestic-made calcitriol combined with calcium was used in management of 24 hypocalcemic patients of hypo- or pseudohypoparathyroidism and relieved their hypocalcemic symptoms and signs with significantly increased serum calcium levels. In 20 patients who were included by the end of this study, serum Ca levels became normal or nearly normal in 80% and 15% of patients. One patient even developed hypercalcemia. Serum P levels became normal in 40% of patients. Supplementation of enough elementary calcium (1–3 g/d) is basic treatment in such patients, but is not enough, especially in patients with moderate to severe hypocalcemia as in this study. Most patients with hypoparathyroidism or pseudohypoparathyroidism who are hypocalcemic must use vitamin D or its analogues. In this study, most patients had taken large dose of calcium (>1 g/d) in local hospitals before participating in the study with poor effect. So we can attribute the improvement of serum Ca levels mostly to calcitriol. Meng et al10 had reported treatment of 19 hypoparathyroid patients with 1α(OH)D3 for 14 weeks, in which blood Ca and iCa levels increased by 23% and 17% respectively, while serum phosphorus levels decreased by 29%. The average levels of serum Ca reached 2.18 mmol/L at the end of the treatment. These observations suggest that active metabolites of vitamin D combined with calcium can effectively improve hypocalcemic symptoms and signs and maintain serum Ca level within or just below the normal interval. Meng et al also found that despite the increase of serum and urinary calcium levels during the treatment, there was no significant increase of urinary hydroxyproline level. Mortensen et al11 conducted a case-control study to examine the effect of long-term vitamin D treatment on calcium and phosphate homeostasis at organ level in hypoparathyroid patients. Similarly, the absolute intestinal calcium absorption was increased while bone resorption rates and bone mineralization rates were very low. Bone histomorphometry study also revealed reduced resorption rate and depth, prolonged resorption period in vitamin D treated hypoparathyroid patients.12 It is suggested that main effect of vitamin D or its active forms of analogues is to promote calcium absorption at intestine, but not stimulate bone calcium mobilization.

Up to date, genuine vitamin D2 (or D3), dihydrotachysterol, alfacalcidol (1α(OH)D3) and calcitriol (1,25(OH)2D3) can be selected for clinical use. Schilling et al13 carried out a retrospective study of 45 patients treated during 8 years. In their department, 1,25(OH)2D3 was the only vitamin D agent administered in treatment of children, while in adults 52%, 28% and 20% were treated with dihydrotachysterol, genuine vitamin D3 and 1,25(OH)2D3, respectively. Genuine vitamin D2 (or D3) is the cheapest vitamin D agent. However, the prodrugs like genuine vitamin D and dihydrotachysterol have long biologic half life with the risk of intoxication after long-term treatment.14–17 Its effect is relatively weak so that larger dose is needed. The time of genuine vitamin D needed to normalize serum calcium levels is 4–8 weeks and duration of effect lasts for 6–12 weeks. 1,25 (OH)2D3 is the biologic active metabolite of vitamin D, which is the most potent agent. It has a short half-life and the time needed to normalize serum Ca level is about 3–7 days, while its effect would vanish 3–7 days after termination of therapy. These characters are helpful to monitor and avoid intoxication of vitamin D.2 In this study, 14 patients were improved significantly by calcitriol at the 2nd week, suggesting calcitriol has a rapid effect to increase serum Ca level. One patient developed hypercalcemia which turned to normal range 2 weeks after adjustment of calcitriol dose, indicating a relative rapid disappearance of its effect after drug withdrawal.

In patients with hypoparathyroidism, PTH deficiency leads to increased excretion of urinary Ca in relation to serum Ca due to decreased resortion of calcium in renal tubule.17,18 In this study we also observed several patients having hypercalciuria during calcitriol treatment. Winer et al19 compared the long-term effect of PTH1–34 with calcitriol in treatment of hypoparathyroidism for 3 years. Throughout the 3-year study period, serum calcium levels were similar in both treatment groups within or just below the normal range. But excretion of urinary calcium was increased significantly in calcitriol group ((5.80±0.27) mmol/L to (8.20±0.51) mmol/L), while urinary calcium excretion was within the normal range from 1–3 year in PTH-treated patients. Their results also supported the effect of PTH deficiency on renal tubule. Long-term hypercalciuria causes nephrolithiasis or nephrocalcinosis, leading to impairment of renal function. So it is not always reasonable to maintain serum calcium levels within complete normal range, and it is necessary to monitor urinary Ca excretion and adjust drug dose during treatment. Thiazide diuretics may be used to decrease urinary Ca excretion if necessary.20

With emerge of human recombinant PTH, it was used in several clinical trials of treatment of hypoparathyroidism. It has the advantage of normalizing serum Ca levels without increasing urinary Ca excretion, reducing the risk of nephrocalcinosis and renal damage. But it has to be injected once or twice daily and more expensive, limiting its long-term and widely application.19,21,22 Research on gene therapy of hypoparathyroidism with hematopoietic stem cells has also been conducted, but only in animal models. There is still a long way for clinical application.23

There are some limitations in this study. First, due to the rarity of this kind of disease and ethical consideration, this study was designed as a self-control study instead of placebo control. But the evaluation of efficacy of treatment mainly based on objective indexes including blood and urinary biochemical markers which would be affected by placebo-effect to a very small extent. We still can attribute the improvement of these patients to calcitriol combined with calcium, but not placebo effect. Second, some patients lived far away from our hospital leading to inconvenience of follow-up and 16.7% (n=4) of patients dropped out from this study, which might affect the final results to a certain extent.

In conclusion, the domestic-made calcitriol combined with calcium can rapidly, effectively and safely elevate serum Ca levels, correct hypocalcemic symptoms and signs in hypoparathyroidism patients. The main side effects include hypercalcemia and hypercalciuria which should be monitored and can be avoided through adjustment of drug dose or administration of thiazide diuretics.

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Keywords:

hypocalcemia; hypoparathyroidism; pseudohypoparathyroidism; calcitriol

© 2009 Chinese Medical Association