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Vitamin D therapy in hypoparathyroidism and pseudohypoparathyroidism: Weight-related dosages for initiation of therapy and maintenance therapy
December 1977
1006
TheJournalofPEDIATRICS
Vitamin D therapy in hypoparathyroidism and pseudohypoparathyroidism" Weight-related dosages for initiation of therapy and maintenance therapy The aims of this study were to determine the dose of vitamin D~ that maintains the serum calcium level within the normal range in hypoparathyroid and pseudohypoparathyroid children and to establish a safe and quickly acting dose for initiating therapy in symptomatic patients. The dose requirement for maintenance therapy was studied in 11 patients and initiation therapy was studied in five newly diagnosed hypocalcemic patients. The results show that (1) the maintenance requirement of vitamin D~ is proportional to body weight and averages 2,000 IU (50 ~g)/kg/day for children of all ages and with all types of hypopamthyroid disorders and that (2) in newly diagnosed symptomatic patients, carefully controlled administration of 8,000 IU (200 Ixg) vitamin DJkg/day for the first one to two weeks corrects hypocalcemia quickly and safely.
H a n s Peter
Kind, M.D., Alan Handysides, M.D., F.R.C.P.(C),
Sang W h a y
Kooh, M.D., Ph.D., F.R.C.P.(C), and
Donald Fraser, M.D., Ph.D.,* Toronto, Ont., C a n a d a
VITAMIN D and related sterols are effective in treating the various forms of hypoparathyroidism and the syndrom e of pseudohypoparathyroidism. 1 The amount of vitamin D needed to maintain the serum calcium of such patients within the normal range is far in excess of the physiologic requirement, but published information on the actual dose requirement is scant. ~ :~ The lack of informatio n on dose requirements for children is particularly disconcerting, since body we!ghts vary greatly with age and c'nange rapidly during growth. Furthermore, no attempts have been made to establish a loading dose of vitamin D that quickly yet safely corrects hypocalcemia in the newly diagnosed symptomatic patient. The aims of the present studies were (1) to determine the maintenance requirement of vitamin D in a group of children and young adults with hyp0parathyroidism and pseudohypoparathyroidism and (2) to find a safe but From the University of Toronto and The Research Institute The Hospital for Sick Children. *Reprint address: The Hospital for Sick Children, 555 University Ave., Toronto, Ont., Canada M5G 1X8.
VoL 91, No. 6, pp. 1006-1010
quickly acting dosage schedule for initiating therapy in the newly diagnosed symptomatic patient. PATIENTS,
METHODS,
AND RESULTS
Table I summarizes the diagnoses and clinical features of the patients and indicates the period during which each patient was investigated. Maintenance requirements were studied in Patients 1 to 11; responses to a schedule for initiating treatment were tested in Patients 12 to 16. Criteria for selection of patients. For inclusion in the study to determine the maintenance requirement, the patients met the following criteria: (1) each received vitamin D2 (ergocalciferol) as the only form of therapy (no aluminium hydroxide nor calcium supplements were administered); (2) the patient and his parents could be relied upon to follow instructions regarding regular and precise dosage; (3) all determinations of serum calcium were conducted in the same laboratory by the same technique; and (4) all follow-up assessments were conducted by one of the authors. Analytical procedures. Serum calcium concentrations were determined by an automated ethylene diaminetetra-
Volume 91 Number 6
Vitamin D therapy in hypoparathyroidism and pseudohypoparathyroidism
10 0 7
Table I. Clinical data for the patients
Diagnosis
Age at diagnosis @r)
Age at start of study @r)
Duration of study (mo)
3/12 13
7 14
21 31
Patient
Sex
l 2
F M
Congenital HP Idiopathic HP
3 4 5 6
F F M M
Idiopathic HP Idiopathic HP Idiopathic HP Postthyroidectomy HP
9 2 14 8
12 4 14 9
21 30 10 42
7 8
F F
Postthyroidectomy HP PHP
14 12
15 14
31 39
9 10
M F
PHP PHP
12 23
12 23
22 11
11 12
F M
PHP PHP
8 11
8 11
11 3
13 14 15 16
F F M F
Postthyroidectomy HP Postthyroidectomy HP Idiopathic HP PHP
17 8 9 5
17 8 9 5
3 3 3 3
Additional features Cleft palate, hare lip, cerebral palsy, mental retardation Chronic keratitis Addison disease since age 5 years Von Recklinghausen neurofibromatosis -Severe mental retardation, postthyroidectomy hypothyroidism Cousin of Patiems 10 and 12. Cousin of Patient 9, sister of Patient 12 Brother of Patient 9, cousin of Patient 10 -Obesity, round face, extraskeletal calcifications, mental retardation
HP = Hypoparathyroidism; PHP = pseudohypoparathyroidism. acetate titration method using calcein indicator,' The range established with this method in our hospital is 9.0 to 10.5 m g / d l for normal children. Studies to determine the maintenance requirement of vitamin D. Procedure. Patients were examined in the Metabolic Outpatient Clinic at regular intervals. At each assessment, body weight was recorded, clinical evidence of hypo- or hypercalcemia was sought, and the serum calcium concentration was determined. Patients in good control were examined every 8 to 12 weeks. If the dosage of vitamin D had recently been adjusted, the patient was assessed at intervals of 4 to 6 weeks. In nine patients the medication was prescribed in liquid form as a standard pharmaceutical preparation containing 100,000 1U (2.5 rag) vitamin D~ per ml (Radiostol liquid, Allen & Hanbury, Toronto, Canada), and the appropriate volume of the vitamin preparation was administered by the parent or patient directly into the mouth from a disposable tuberculin syringe, This procedure was adopted because we had demonstrated that as much as 20% variation in the size of the dose could occur when using a dropper. In two patients (Patients 2 and 6), the vitamin D2 was administered as capsules containing 50,000 1U (1.25 mg) per capsule (Ostoforte, Frosst, Montreal, Canada). However, administration of vitamin D in capsule form lacks the
adaptability that we consider important for good biochemical control. Patients remained on their usual selfselected diets. A serum calcium value within the range of 8.5 to 10.0 m g / d l was accepted as satisfactory. Two successive values above or below this range, or a rapid change in serum calcium concentration within the range, was indication for changing the dosage, usually by a 15 to 20% increase or decrease in the dose. Calcium values were included in the study only if a particular dose of vitamin D had been in effect for at least six weeks. Results. Fig. 1 shows the results of 71 individual determinations of serum calcium independent of diagnosis for Patients 1 to 11, plotted against the corresponding maintenance dose of vitamin D~ expressed as dose/kilogram body weight/day. Also plotted is the initial serum calcium value of each patient prior to treatment. Excluding the initial and two hypercalcemic values, regression analysis of serum calcium values in relation to vitamin D showed a significant positive correlation (y = 7.6 + 0.007 x, r = 0.58; P < 0.01). The regression line and the 95% confidence limits are superimposed on the plotted data. Doses of vitamin D~ that controlled the mean serum calcium within the limits of 8.5 to 10.5 m g / d l ranged from 1,300 to 2,600 I U / k g / d a y (33 to 65 /~g/kg/ day).
10 0 8
Kind et al.
The Journal of Pediatrics December 1977
Serum Ca
Ca
Serum
mg/dl
16mg/dl
!
14--
mg/dl 14-13--
13--
12--
12--
11--
-~-*"; . . . . . : : . . . . .
10--
+2 SD~--
*
*~=* ~
+2 SD
**~MEAN
9--
11--
...............
10--
..... IA~ O ....--/ 9
9-M E A 9eN v~,
8--
**!
.,---2SD
-2 S O - ' * . . . .
7--
Z ~
io
8--
§
SD
MEAN ~2 SD
7--
6--
6--
5--
5--
4--
4-
3--
3-f 0
I 500
I 1000
0.025
I 1500
i 2000
0.050
I 2500
I 3000 I U / k g / d a y
0.075 mg/kg/day
0
I 500
I 1000
0025
I 1500
I 2000
0050
I 2500
I 3000
IU/kg/day
0.075
mg/kg/day
Fig. 1. Graph showing serum calcium Values in 11 patients with hypoparathyroidism and pseudohypoparathyroidism plotted against the corresponding daily maintenance dose of vitamin D. Seventy-one serum calcium determinations during therapy are plotted independently of diagnosis, and the pretreatment value of each patient is shown. The regression' line and 95% confidence limits of the data excluding the pretreatment and the two hypercalcemic values are indicated.
Fig. 2. Graph showing the mean serum calcium value for each Of the I1 patients over the entire period of observation, plotted against the corresponding mean daily dosage of vitamin D for that patient. The diagnosis of each patient is indicated: idiopathic hypoparathyroidism, m; postoperative hypoparathyroidism, o; pseudohypoparathyroidsm, h The regression line and the 95% confidence limits for the data shown in Fig. 1 are superimposed.
Fig. 1 shows that a vitamin D~ intake of 2,000 I U / k g / day results on the average in a serum Calcium concentration Of 9.0 mg/dl, and that 95% of the values obtained in our 11 patients with this dose of vitamin D fell within the safe range of 7.6 to 10.5 mg/dl. During the p e r i o d of study, two individuals (Patients 3 and 8), developed vitamin D intoxication, with serum calcium levels of 12.4 and 16 mg/dl, respectively (Fig. 1). In both instances, the dose of vitamin D was greater than 2,700 I U / k g / d a y (68 ~g/kg/day). Serum calcium returned tO normal within a few days when vitamin D was withheld, and the patients were subsequently controlled on doses 15% lower than those which had caused hypercalcemia. Fig. 2 shows the mean serum calcium concentration for each of the 11 patients over the entire period of observation, plotted against the corresponding mean dosage of Vitamin D for that patient. The diagnosis of each patient is designated. Fig. 2 shows that vitamin D requirement is independent of the type of parathyroid disturbance.
was discontinued when the serum calcium concentration reached 9.0 mg/dl. In one of the patients, vitamin treatment was resumed immediately, using the maintenance dose of 2,000 I U / k g / d a y ; in the four other patients the maintenance dose was commenced after withholding all vitamin D treatment for three days. Results. The responses of the patients to loading doses of vitamin D2 are shown in Fig. 3, A. The concentrations of serum calcium started to increase within two days and reached 9.0 mg/dl after periods ranging from eight to 16 days. When, in four patients, vitamin D was then withheld for three days tO document whether serum calcium levels would continue to rise after stopping these high doses of Vitamin D (Fig. 3, B), the serum calcium concentration remained stable at approximately 9 mg/dl. When treatment was resumed using the maintenance dosage of 2,000 I U / k g / d a y (Fig. 3, C), serum calcium concentrations remained between 9.0 and 10.0 mg/dl; none of the patients needed further adjustments in their daily doses during the succeeding eight-week period of observation.
Establishing a dosage schedule for initiating therapy in patients with symptomatic hypocalcemia. Procedure. We have investigated, under closely controlled conditions; the responses of five untreated patients with hypocalcemia (Table I, Patients 12 to 16) to 8,000 iU vitamin D J k g / d a y (200/~g/kg/day). This dose was four times the maintenance dose. During treatment with these loading doses of vitamin D, serum calcium determinations were performed daily. The loading dose
DISCUSSION Experience has shown that vitamin D and related sterols are effective for treating the various forms of hypoparathyroidism and pseudohypoparathyroidism. Although recent studies have shown that la,25-dihydroxyvi-
Volume 91 Number 6
Vitamin D therapy in hypoparathyroidism and pseudohypoparathyroidism
NO ITHERAPY VIT-D:~ 2000 IU/kg/day
8000 IU/kg/dcvy
VITAMIN-D2
10 0 9
I
I
l
Serum Ca
mg/dl 10-
2"
9-
~:
87654 - //
0
///
//
///
B
A
5
I 10 DAYS
m 15
FT'T"T12 3 0 DAYS
C I 4 WEEKS
I 8
Fig. 3. Serum calcium concentrations in five previously untreated patients, A, during loading doses of vitamin D, B, after discontinuing loading doses, and C, on maintenance therapy. tamin D~ and its analogue la,hydroxyvitamin D~, are effective in very small doses) -~ these agents are not yet readily available, and the advantages and disadvantages of using them in long-term management of hypoparathyroidism and pseudohypoparathyroidism have not yet been adequately assessed. At the present time, vitamin D~, vitamin D:,, and dihydrotachysterolT M are the most widely used therapeutic agents. The least expensive, and most readily available preparation in North America, is vitamin D~, and we have employed this agent in our patients. Vitamin D~ was effective in all individuals in the present series. Indeed, in a much larger series of more than 40 hypoparathyroid and pseudohypoparathyroid patients treated at this hospital during the past 25 years, none has developed the marked degree of refractoriness occasionally reported.l-'. ,:~ In this selected group of patients, we have achieved satisfactory control of the serum calcium and phosphate levels without recourse to oral calcium supplements, aluminium hydroxide gel, or special diet. Once the proper maintenance dose has been established for a given patient, the requirement of vitamin D remains quite constant and requires only occasional minor alteration provided that the dosage is adjusted in relation to the weight of the patient. Our experience indicates, however, that measurement of serum calcium and phosphorus concentrations at intervals not exceeding four months is an important precaution. If the value of the serum calcium falls outside the normal range, the therapeutic dose should be adjusted. A 15 to 20% increase or decrease in the daily dose is usually sufficient to increase or decrease the serum calcium concentration by 0.5 mg/dl. These relatively small dosage changes can be achieved most readily by
using a high potency preparation of vitamin D in liquid form which is measured into the patient's mouth from a disposable tt)berculin syringe. Capsule formulations lack the flexibility needed for fine adjustment of dosage. In the standard textbooks, dosage recommendations are expressed in ranges; the size of the patient has not been considered and the appropriate dose was established by trial and error, usually over several months. No specific dosage schedules have been suggested for initiating therapy. Based on our study, we present the following recommendations for initiating vitamin D therapy in patients with symptomatic hypocalcemia and for maintenance therapy in hypoparathyroidism and pseudohypoparathyroidism. In our experience, vitamins D., and D:, are of equal potency in the two conditions. We believe that our recommendations are applicable to patients of all ages. RECOMMENDATIONS To initiate vitamin D therapy in patients with symptomatic hypocalcemia. In patients with symptomatic hypocalcemia, administer vitamin D~, 8,000 I U / k g / d a y (200 /~g/kg/day) by mouth until the serum calcium concentration reaches 9.0 mg/dl. Determine the serum calcium concentration daily. Supportive treatment with an infusion of calcium gluconate is recommended for two or three days. Normocalcemia is usually attained within one to two weeks. As soon as the serum calcium level reaches 9.0 mg/dl, immediately reduce the dose of vitamin D to 2,000 I U / k g / d a y (50/~g/kg/day) for maintenance. Maintenance therapy. The best estimate of the maintenance requirement of vitamin D2 for a new patient with hypoparathyroidism or pseudohypoparathyroidism i s 2,000 I U / k g / d a y (50 /~g/kg/day). After starting this maintenance dose the next outpatient evaluation should
10 10
Kind et al.
take place in four to six weeks. Later, evaluations should be at three- to four-month intervals, as long as treatment is in effect. For patients who live remote from the clinic, provision of return-addressed mailing tubes by which serum samples can be conveniently shipped for analysis is a useful procedure. If the serum calcium is outside the desired level (we strive to maintain serum calcium concentration between 8.5 and 10.0 btg/dl), the dosage should be adjusted. If the patient is hypocalcemic, the daily dose of vitamin D is increased by 15 to 20% of the previous dose. If the patient is hypercalcemic, vitamin D is discontinued immediately and other measures are employed to treat hypercalcemia (extra intake of fluids, low-calcium diet, etc), while the serum calcium level is monitored frequently. Serum calcium usually becomes normal within a few days. W h e n it has returned to the desired level, vitamin D therapy is restarted, using a daily dose 15 to 20% less than previously. In either instance, the effect of the new dosage is evaluated within six weeks following the change in dosage, and at longer intervals thereafter. REFERENCES
1. Fraser D: Disturbances of parathyroid hormone and calcitonin, in Forfar JO, and Arneil GC, editors: Textbook of paediatrics. Edinburgh, 1973, Churchill Livingstone, pp 1117-1132. 2. Ireland AW, Clubb .IS, Neale FC, Posen S, and Reeve TS: The calciferol requirements of patients with surgical hypoparathyroidism, Ann Intern Med 69:81, 1968. 3. Parfitt AM: Vitamin D treatment in hypoparathyroidism, Lancet 2:614, 1970.
The Journal of Pediatrics December 1977
4. Diehl H, and Ellingboe JL: Indicator for titration of calcium in presence of magnesium using disodium ethylenediamine tetra-acetate, Anal Chem 28:882, 1956. 5. Russell RGG, Smith R, Walton R J, Preston C, Basson R, Henderson RG, and Normal AW: 1,25-Dihydroxycholecalciferol and lahydroxycholecalciferol in hypoparathyroidism, Lancet 2:14, 1974. 6. Kind HP, Prader A, DeLuca HF, and Gugler E: lc~Hydroxycholecalciferol in hypoparathyroidism and pseudohypoparathyroidism, Lancet 1:1145, 1975. 7. Kooh SW, Fraser D, DeLuca HF, Holick MF, Belsey RE, Clark MB, and Murray TM: Treatment of hypoparathyroidism and pseudohypoparathyroidism with metabolites of vitamin D: evidence for impaired conversion of 25-hydroxyvitamin D to la25-dihydroxyvitamin D, N Engl J Med 293:840, 1975. 8. Drezner MK, Neelon FA, Haussler M, MacPherson HT, and Lebovitz HE: 1,25-Dihydroxycholecalciferol deficiency; the probable cause of hypocalcemia and metabolic bone disease in pseudohypoparathyroidism, J Clin Endocrinol 42:621; 1976. 9. Harrison HE, Lifshitz F, and Blizzard RM: Comparison between crystalline dihydrotachysterol and calciferol in patients requiring pharmacologic vitamin D therapy, N Engl J Med 276:894, 1967. 10. Dymling JF, and Ryd H: Crystalline dihydrotachysterol (Dygratyl) in the treatment of hypoparathyroidism, Acta Med Scand 184:333, 1968. 11. MacBryde CM: The treatment of parathyroid tetany with dihydrotachysterol, JAMA 111:304, 1938. 12. Dent CE, Harper CM, Morgans ME, Philpot GR, and Trotter WR: Insensitivity to vitamin D developing during the treatment of postoperative tetany, Lancet 2:687, 1955. t3. Pak CYC, DeLuca HF, Chavez de los Rios JM, Suda T, Ruskin B, and Delea CS: Treatment of vitamin D-resistant hypoparathyroidism with 25-hydroxycholecalciferol, Arch Intern Med 126:239, 1970.
1006
TheJournalofPEDIATRICS
Vitamin D therapy in hypoparathyroidism and pseudohypoparathyroidism" Weight-related dosages for initiation of therapy and maintenance therapy The aims of this study were to determine the dose of vitamin D~ that maintains the serum calcium level within the normal range in hypoparathyroid and pseudohypoparathyroid children and to establish a safe and quickly acting dose for initiating therapy in symptomatic patients. The dose requirement for maintenance therapy was studied in 11 patients and initiation therapy was studied in five newly diagnosed hypocalcemic patients. The results show that (1) the maintenance requirement of vitamin D~ is proportional to body weight and averages 2,000 IU (50 ~g)/kg/day for children of all ages and with all types of hypopamthyroid disorders and that (2) in newly diagnosed symptomatic patients, carefully controlled administration of 8,000 IU (200 Ixg) vitamin DJkg/day for the first one to two weeks corrects hypocalcemia quickly and safely.
H a n s Peter
Kind, M.D., Alan Handysides, M.D., F.R.C.P.(C),
Sang W h a y
Kooh, M.D., Ph.D., F.R.C.P.(C), and
Donald Fraser, M.D., Ph.D.,* Toronto, Ont., C a n a d a
VITAMIN D and related sterols are effective in treating the various forms of hypoparathyroidism and the syndrom e of pseudohypoparathyroidism. 1 The amount of vitamin D needed to maintain the serum calcium of such patients within the normal range is far in excess of the physiologic requirement, but published information on the actual dose requirement is scant. ~ :~ The lack of informatio n on dose requirements for children is particularly disconcerting, since body we!ghts vary greatly with age and c'nange rapidly during growth. Furthermore, no attempts have been made to establish a loading dose of vitamin D that quickly yet safely corrects hypocalcemia in the newly diagnosed symptomatic patient. The aims of the present studies were (1) to determine the maintenance requirement of vitamin D in a group of children and young adults with hyp0parathyroidism and pseudohypoparathyroidism and (2) to find a safe but From the University of Toronto and The Research Institute The Hospital for Sick Children. *Reprint address: The Hospital for Sick Children, 555 University Ave., Toronto, Ont., Canada M5G 1X8.
VoL 91, No. 6, pp. 1006-1010
quickly acting dosage schedule for initiating therapy in the newly diagnosed symptomatic patient. PATIENTS,
METHODS,
AND RESULTS
Table I summarizes the diagnoses and clinical features of the patients and indicates the period during which each patient was investigated. Maintenance requirements were studied in Patients 1 to 11; responses to a schedule for initiating treatment were tested in Patients 12 to 16. Criteria for selection of patients. For inclusion in the study to determine the maintenance requirement, the patients met the following criteria: (1) each received vitamin D2 (ergocalciferol) as the only form of therapy (no aluminium hydroxide nor calcium supplements were administered); (2) the patient and his parents could be relied upon to follow instructions regarding regular and precise dosage; (3) all determinations of serum calcium were conducted in the same laboratory by the same technique; and (4) all follow-up assessments were conducted by one of the authors. Analytical procedures. Serum calcium concentrations were determined by an automated ethylene diaminetetra-
Volume 91 Number 6
Vitamin D therapy in hypoparathyroidism and pseudohypoparathyroidism
10 0 7
Table I. Clinical data for the patients
Diagnosis
Age at diagnosis @r)
Age at start of study @r)
Duration of study (mo)
3/12 13
7 14
21 31
Patient
Sex
l 2
F M
Congenital HP Idiopathic HP
3 4 5 6
F F M M
Idiopathic HP Idiopathic HP Idiopathic HP Postthyroidectomy HP
9 2 14 8
12 4 14 9
21 30 10 42
7 8
F F
Postthyroidectomy HP PHP
14 12
15 14
31 39
9 10
M F
PHP PHP
12 23
12 23
22 11
11 12
F M
PHP PHP
8 11
8 11
11 3
13 14 15 16
F F M F
Postthyroidectomy HP Postthyroidectomy HP Idiopathic HP PHP
17 8 9 5
17 8 9 5
3 3 3 3
Additional features Cleft palate, hare lip, cerebral palsy, mental retardation Chronic keratitis Addison disease since age 5 years Von Recklinghausen neurofibromatosis -Severe mental retardation, postthyroidectomy hypothyroidism Cousin of Patiems 10 and 12. Cousin of Patient 9, sister of Patient 12 Brother of Patient 9, cousin of Patient 10 -Obesity, round face, extraskeletal calcifications, mental retardation
HP = Hypoparathyroidism; PHP = pseudohypoparathyroidism. acetate titration method using calcein indicator,' The range established with this method in our hospital is 9.0 to 10.5 m g / d l for normal children. Studies to determine the maintenance requirement of vitamin D. Procedure. Patients were examined in the Metabolic Outpatient Clinic at regular intervals. At each assessment, body weight was recorded, clinical evidence of hypo- or hypercalcemia was sought, and the serum calcium concentration was determined. Patients in good control were examined every 8 to 12 weeks. If the dosage of vitamin D had recently been adjusted, the patient was assessed at intervals of 4 to 6 weeks. In nine patients the medication was prescribed in liquid form as a standard pharmaceutical preparation containing 100,000 1U (2.5 rag) vitamin D~ per ml (Radiostol liquid, Allen & Hanbury, Toronto, Canada), and the appropriate volume of the vitamin preparation was administered by the parent or patient directly into the mouth from a disposable tuberculin syringe, This procedure was adopted because we had demonstrated that as much as 20% variation in the size of the dose could occur when using a dropper. In two patients (Patients 2 and 6), the vitamin D2 was administered as capsules containing 50,000 1U (1.25 mg) per capsule (Ostoforte, Frosst, Montreal, Canada). However, administration of vitamin D in capsule form lacks the
adaptability that we consider important for good biochemical control. Patients remained on their usual selfselected diets. A serum calcium value within the range of 8.5 to 10.0 m g / d l was accepted as satisfactory. Two successive values above or below this range, or a rapid change in serum calcium concentration within the range, was indication for changing the dosage, usually by a 15 to 20% increase or decrease in the dose. Calcium values were included in the study only if a particular dose of vitamin D had been in effect for at least six weeks. Results. Fig. 1 shows the results of 71 individual determinations of serum calcium independent of diagnosis for Patients 1 to 11, plotted against the corresponding maintenance dose of vitamin D~ expressed as dose/kilogram body weight/day. Also plotted is the initial serum calcium value of each patient prior to treatment. Excluding the initial and two hypercalcemic values, regression analysis of serum calcium values in relation to vitamin D showed a significant positive correlation (y = 7.6 + 0.007 x, r = 0.58; P < 0.01). The regression line and the 95% confidence limits are superimposed on the plotted data. Doses of vitamin D~ that controlled the mean serum calcium within the limits of 8.5 to 10.5 m g / d l ranged from 1,300 to 2,600 I U / k g / d a y (33 to 65 /~g/kg/ day).
10 0 8
Kind et al.
The Journal of Pediatrics December 1977
Serum Ca
Ca
Serum
mg/dl
16mg/dl
!
14--
mg/dl 14-13--
13--
12--
12--
11--
-~-*"; . . . . . : : . . . . .
10--
+2 SD~--
*
*~=* ~
+2 SD
**~MEAN
9--
11--
...............
10--
..... IA~ O ....--/ 9
9-M E A 9eN v~,
8--
**!
.,---2SD
-2 S O - ' * . . . .
7--
Z ~
io
8--
§
SD
MEAN ~2 SD
7--
6--
6--
5--
5--
4--
4-
3--
3-f 0
I 500
I 1000
0.025
I 1500
i 2000
0.050
I 2500
I 3000 I U / k g / d a y
0.075 mg/kg/day
0
I 500
I 1000
0025
I 1500
I 2000
0050
I 2500
I 3000
IU/kg/day
0.075
mg/kg/day
Fig. 1. Graph showing serum calcium Values in 11 patients with hypoparathyroidism and pseudohypoparathyroidism plotted against the corresponding daily maintenance dose of vitamin D. Seventy-one serum calcium determinations during therapy are plotted independently of diagnosis, and the pretreatment value of each patient is shown. The regression' line and 95% confidence limits of the data excluding the pretreatment and the two hypercalcemic values are indicated.
Fig. 2. Graph showing the mean serum calcium value for each Of the I1 patients over the entire period of observation, plotted against the corresponding mean daily dosage of vitamin D for that patient. The diagnosis of each patient is indicated: idiopathic hypoparathyroidism, m; postoperative hypoparathyroidism, o; pseudohypoparathyroidsm, h The regression line and the 95% confidence limits for the data shown in Fig. 1 are superimposed.
Fig. 1 shows that a vitamin D~ intake of 2,000 I U / k g / day results on the average in a serum Calcium concentration Of 9.0 mg/dl, and that 95% of the values obtained in our 11 patients with this dose of vitamin D fell within the safe range of 7.6 to 10.5 mg/dl. During the p e r i o d of study, two individuals (Patients 3 and 8), developed vitamin D intoxication, with serum calcium levels of 12.4 and 16 mg/dl, respectively (Fig. 1). In both instances, the dose of vitamin D was greater than 2,700 I U / k g / d a y (68 ~g/kg/day). Serum calcium returned tO normal within a few days when vitamin D was withheld, and the patients were subsequently controlled on doses 15% lower than those which had caused hypercalcemia. Fig. 2 shows the mean serum calcium concentration for each of the 11 patients over the entire period of observation, plotted against the corresponding mean dosage of Vitamin D for that patient. The diagnosis of each patient is designated. Fig. 2 shows that vitamin D requirement is independent of the type of parathyroid disturbance.
was discontinued when the serum calcium concentration reached 9.0 mg/dl. In one of the patients, vitamin treatment was resumed immediately, using the maintenance dose of 2,000 I U / k g / d a y ; in the four other patients the maintenance dose was commenced after withholding all vitamin D treatment for three days. Results. The responses of the patients to loading doses of vitamin D2 are shown in Fig. 3, A. The concentrations of serum calcium started to increase within two days and reached 9.0 mg/dl after periods ranging from eight to 16 days. When, in four patients, vitamin D was then withheld for three days tO document whether serum calcium levels would continue to rise after stopping these high doses of Vitamin D (Fig. 3, B), the serum calcium concentration remained stable at approximately 9 mg/dl. When treatment was resumed using the maintenance dosage of 2,000 I U / k g / d a y (Fig. 3, C), serum calcium concentrations remained between 9.0 and 10.0 mg/dl; none of the patients needed further adjustments in their daily doses during the succeeding eight-week period of observation.
Establishing a dosage schedule for initiating therapy in patients with symptomatic hypocalcemia. Procedure. We have investigated, under closely controlled conditions; the responses of five untreated patients with hypocalcemia (Table I, Patients 12 to 16) to 8,000 iU vitamin D J k g / d a y (200/~g/kg/day). This dose was four times the maintenance dose. During treatment with these loading doses of vitamin D, serum calcium determinations were performed daily. The loading dose
DISCUSSION Experience has shown that vitamin D and related sterols are effective for treating the various forms of hypoparathyroidism and pseudohypoparathyroidism. Although recent studies have shown that la,25-dihydroxyvi-
Volume 91 Number 6
Vitamin D therapy in hypoparathyroidism and pseudohypoparathyroidism
NO ITHERAPY VIT-D:~ 2000 IU/kg/day
8000 IU/kg/dcvy
VITAMIN-D2
10 0 9
I
I
l
Serum Ca
mg/dl 10-
2"
9-
~:
87654 - //
0
///
//
///
B
A
5
I 10 DAYS
m 15
FT'T"T12 3 0 DAYS
C I 4 WEEKS
I 8
Fig. 3. Serum calcium concentrations in five previously untreated patients, A, during loading doses of vitamin D, B, after discontinuing loading doses, and C, on maintenance therapy. tamin D~ and its analogue la,hydroxyvitamin D~, are effective in very small doses) -~ these agents are not yet readily available, and the advantages and disadvantages of using them in long-term management of hypoparathyroidism and pseudohypoparathyroidism have not yet been adequately assessed. At the present time, vitamin D~, vitamin D:,, and dihydrotachysterolT M are the most widely used therapeutic agents. The least expensive, and most readily available preparation in North America, is vitamin D~, and we have employed this agent in our patients. Vitamin D~ was effective in all individuals in the present series. Indeed, in a much larger series of more than 40 hypoparathyroid and pseudohypoparathyroid patients treated at this hospital during the past 25 years, none has developed the marked degree of refractoriness occasionally reported.l-'. ,:~ In this selected group of patients, we have achieved satisfactory control of the serum calcium and phosphate levels without recourse to oral calcium supplements, aluminium hydroxide gel, or special diet. Once the proper maintenance dose has been established for a given patient, the requirement of vitamin D remains quite constant and requires only occasional minor alteration provided that the dosage is adjusted in relation to the weight of the patient. Our experience indicates, however, that measurement of serum calcium and phosphorus concentrations at intervals not exceeding four months is an important precaution. If the value of the serum calcium falls outside the normal range, the therapeutic dose should be adjusted. A 15 to 20% increase or decrease in the daily dose is usually sufficient to increase or decrease the serum calcium concentration by 0.5 mg/dl. These relatively small dosage changes can be achieved most readily by
using a high potency preparation of vitamin D in liquid form which is measured into the patient's mouth from a disposable tt)berculin syringe. Capsule formulations lack the flexibility needed for fine adjustment of dosage. In the standard textbooks, dosage recommendations are expressed in ranges; the size of the patient has not been considered and the appropriate dose was established by trial and error, usually over several months. No specific dosage schedules have been suggested for initiating therapy. Based on our study, we present the following recommendations for initiating vitamin D therapy in patients with symptomatic hypocalcemia and for maintenance therapy in hypoparathyroidism and pseudohypoparathyroidism. In our experience, vitamins D., and D:, are of equal potency in the two conditions. We believe that our recommendations are applicable to patients of all ages. RECOMMENDATIONS To initiate vitamin D therapy in patients with symptomatic hypocalcemia. In patients with symptomatic hypocalcemia, administer vitamin D~, 8,000 I U / k g / d a y (200 /~g/kg/day) by mouth until the serum calcium concentration reaches 9.0 mg/dl. Determine the serum calcium concentration daily. Supportive treatment with an infusion of calcium gluconate is recommended for two or three days. Normocalcemia is usually attained within one to two weeks. As soon as the serum calcium level reaches 9.0 mg/dl, immediately reduce the dose of vitamin D to 2,000 I U / k g / d a y (50/~g/kg/day) for maintenance. Maintenance therapy. The best estimate of the maintenance requirement of vitamin D2 for a new patient with hypoparathyroidism or pseudohypoparathyroidism i s 2,000 I U / k g / d a y (50 /~g/kg/day). After starting this maintenance dose the next outpatient evaluation should
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Kind et al.
take place in four to six weeks. Later, evaluations should be at three- to four-month intervals, as long as treatment is in effect. For patients who live remote from the clinic, provision of return-addressed mailing tubes by which serum samples can be conveniently shipped for analysis is a useful procedure. If the serum calcium is outside the desired level (we strive to maintain serum calcium concentration between 8.5 and 10.0 btg/dl), the dosage should be adjusted. If the patient is hypocalcemic, the daily dose of vitamin D is increased by 15 to 20% of the previous dose. If the patient is hypercalcemic, vitamin D is discontinued immediately and other measures are employed to treat hypercalcemia (extra intake of fluids, low-calcium diet, etc), while the serum calcium level is monitored frequently. Serum calcium usually becomes normal within a few days. W h e n it has returned to the desired level, vitamin D therapy is restarted, using a daily dose 15 to 20% less than previously. In either instance, the effect of the new dosage is evaluated within six weeks following the change in dosage, and at longer intervals thereafter. REFERENCES
1. Fraser D: Disturbances of parathyroid hormone and calcitonin, in Forfar JO, and Arneil GC, editors: Textbook of paediatrics. Edinburgh, 1973, Churchill Livingstone, pp 1117-1132. 2. Ireland AW, Clubb .IS, Neale FC, Posen S, and Reeve TS: The calciferol requirements of patients with surgical hypoparathyroidism, Ann Intern Med 69:81, 1968. 3. Parfitt AM: Vitamin D treatment in hypoparathyroidism, Lancet 2:614, 1970.
The Journal of Pediatrics December 1977
4. Diehl H, and Ellingboe JL: Indicator for titration of calcium in presence of magnesium using disodium ethylenediamine tetra-acetate, Anal Chem 28:882, 1956. 5. Russell RGG, Smith R, Walton R J, Preston C, Basson R, Henderson RG, and Normal AW: 1,25-Dihydroxycholecalciferol and lahydroxycholecalciferol in hypoparathyroidism, Lancet 2:14, 1974. 6. Kind HP, Prader A, DeLuca HF, and Gugler E: lc~Hydroxycholecalciferol in hypoparathyroidism and pseudohypoparathyroidism, Lancet 1:1145, 1975. 7. Kooh SW, Fraser D, DeLuca HF, Holick MF, Belsey RE, Clark MB, and Murray TM: Treatment of hypoparathyroidism and pseudohypoparathyroidism with metabolites of vitamin D: evidence for impaired conversion of 25-hydroxyvitamin D to la25-dihydroxyvitamin D, N Engl J Med 293:840, 1975. 8. Drezner MK, Neelon FA, Haussler M, MacPherson HT, and Lebovitz HE: 1,25-Dihydroxycholecalciferol deficiency; the probable cause of hypocalcemia and metabolic bone disease in pseudohypoparathyroidism, J Clin Endocrinol 42:621; 1976. 9. Harrison HE, Lifshitz F, and Blizzard RM: Comparison between crystalline dihydrotachysterol and calciferol in patients requiring pharmacologic vitamin D therapy, N Engl J Med 276:894, 1967. 10. Dymling JF, and Ryd H: Crystalline dihydrotachysterol (Dygratyl) in the treatment of hypoparathyroidism, Acta Med Scand 184:333, 1968. 11. MacBryde CM: The treatment of parathyroid tetany with dihydrotachysterol, JAMA 111:304, 1938. 12. Dent CE, Harper CM, Morgans ME, Philpot GR, and Trotter WR: Insensitivity to vitamin D developing during the treatment of postoperative tetany, Lancet 2:687, 1955. t3. Pak CYC, DeLuca HF, Chavez de los Rios JM, Suda T, Ruskin B, and Delea CS: Treatment of vitamin D-resistant hypoparathyroidism with 25-hydroxycholecalciferol, Arch Intern Med 126:239, 1970.