ORIGINAL
ARTICLE
E n d o c r i n e
C a r e
Effects of Once Versus Twice-Daily Parathyroid
Hormone 1–34 Therapy in Children with
Hypoparathyroidism
Karen K. Winer, Ninet Sinaii, Donna Peterson, Bruno Sainz, Jr., and Gordon B. Cutler, Jr.
National Institute of Child Health and Human Development (K.K.W., D.P., B.S., G.B.C.), National Institutes of Health, Bethesda, Maryland
20892-7510; and Biostatistics and Clinical Epidemiology Service (N.S.), National Institutes of Health Clinical Center, Bethesda, Maryland
20892
Context: Hypoparathyroidism is among the few hormonal insufficiency states not treated with
replacement of the missing hormone. Long-term conventional therapy with vitamin D and analogs
may lead to nephrocalcinosis and renal insufficiency.
Objective: Our objective was to compare the response of once-daily vs. twice-daily PTH 1–34 treatment in children with hypoparathyroidism.
Setting: The study was conducted at a clinical research center.
Subjects: Fourteen children ages 4 –17 yr with chronic hypoparathyroidism were studied.
Study Design: This was a randomized cross-over trial, lasting 28 wk, which compared two dose
regimens, once-daily vs. twice-daily PTH1–34. Each 14-wk study arm was divided into a 2-wk inpatient dose-adjustment phase and a 12-wk outpatient phase.
Results: Mean predose serum calcium was maintained at levels just below the normal range.
Repeated serum measures over a 24-h period showed that twice-daily PTH 1–34 increased serum
calcium and magnesium levels more effectively than a once-daily dose. This was especially evident
during the second half of the day (12–24 h). PTH 1–34 normalized mean 24-h urine calcium excretion on both treatment schedules. This was achieved with half the PTH 1–34 dose during the
twice-daily regimen compared with the once-daily regimen (twice-daily, 25 ⫾15 ␮g/d vs. oncedaily, 58 ⫾ 28 ␮g/d; P ⬍ 0.001).
Conclusions: We conclude that a twice-daily PTH 1–34 regimen provides a more effective treatment
of hypoparathyroidism compared with once-daily treatment because it reduces the variation in
serum calcium levels and accomplishes this at a lower total daily PTH 1–34 dose. The results showed,
as in the previous study of adult patients with hypoparathyroidism, that a twice-daily regimen
produced significantly improved metabolic control compared with once-daily PTH 1–34. (J Clin
Endocrinol Metab 93: 3389 –3395, 2008)
E
xperimental synthetic human PTH 1–34 replacement therapy in adults with hypoparathyroidism maintains serum
calcium in the normal range and reduces urine calcium excretion
(1–3). This therapy, however, is not yet approved for the treatment of primary hypoparathyroidism. Unlike most hormone in-
sufficiency states, primary hypoparathyroidism is not treated by
replacing the missing hormone. Conventional therapy with 1,25
dihydroxycholecalciferol (calcitriol), or other vitamin D analogs, normalizes serum calcium but does not have the renal calcium-retaining effect needed to normalize urine calcium. Thus,
0021-972X/08/$15.00/0
Abbreviations: APS-1, Autoimmune polyglandular failure syndrome type 1; rhPTH, recombinant human PTH 1–34.
Printed in U.S.A.
Copyright © 2008 by The Endocrine Society
doi: 10.1210/jc.2007-2552 Received November 19, 2007. Accepted May 7, 2008.
First Published Online May 20, 2008
For editorial see page 3307
J Clin Endocrinol Metab, September 2008, 93(9):3389 –3395
jcem.endojournals.org
3389
⫺
⫺
⫺
⫺
⫹
⫺
⫺
⫹
⫹
⫹
⫺
⫺
⫺
⫺
66
86
112
108
98
124
138
70
66
87
89
119
94
110
Patients were receiving calcitriol and supplemental calcium at the time of these studies.
Normal range in parenthesis.
Corrected for height and weight.
a
b
c
⫺, Negative; ⫹, positive; APS-1, Autoimmunepolyglandular failure type 1; CaR, calcium receptor mutation; CT, computed tomography; F, female; M, male.
3.9
1.08
4.01
7.08
7.00
3.58
3.3
2.71
3.91
4.21
9.91
3.95
3.3
8.54
0.55
0.71
0.79
0.77
0.75
0.75
0.88
0.84
0.69
0.81
0.80
0.77
0.89
0.81
2.16
3.21
2.26
1.95
1.78
1.97
2.55
1.95
2.91
2.69
1.87
1.95
2.06
1.88
2
1.92
2.02
2.22
2.3
2.14
2.12
2.5
1.7
1.8
2.25
2.02
2.0
2.2
5
1
3
2
1
1
1
4
11
9
4
1
2
8
CaR
Idiopathic
Idiopathic
APS-1
APS-1
Postsurgical
Idiopathic
Idiopathic
Idiopathic
Idiopathic
APS-1
APS-1
Idiopathic
APS-1
Diagnosis
Sex
F
M
M
M
M
M
M
F
F
M
M
M
M
F
Creatinine
clearance ml/min
(90 –125)c
Urine calcium
mmol/24 h
(1.25– 6.25)
Magnesium
mmol/liter
(0.65–1.05)
Phosphorus
mmol/liter
(0.8 –1.6)
Calcium mmol/liter
(2.05–2.5)b
6
11
17
7
13
8
11
4
11
9
9
5
6
11
Fourteen children ages 4 –17 yr that participated in the study. All
subjects (Table 1) were diagnosed with hypoparathyroidism before study
entry by low levels of intact PTH during hypocalcemia (data not shown).
A
B
C
D
E
F
G
H
I
J
K
L
M
N
Subjects
Patientsa
Subjects and Methods
Duration of
hypoparathyroidism
(yr)
patients with hypoparathyroidism, who are treated with vitamin
D analogs, have a tendency toward hypercalciuria. Eventually,
this may lead to nephrocalcinosis, nephrolithiasis, or renal insufficiency (4 –14).
PTH 1–34 was first administered for the diagnosis of
pseudohypoparathyroidism, which is marked by decreased urinary cAMP response to PTH administration. PTH 1–34 was then
used as an experimental treatment for osteoporosis (15–18) and
has recently been approved for therapeutic use in adults with this
disorder. Most of the data regarding the safety and efficacy of
PTH 1–34 administration in adults are from osteoporosis treatment studies. Animal toxicity studies have raised concerns regarding dose-dependent PTH effects on the bone. Long-term,
supraphysiological doses of recombinant human PTH 1–34
(rhPTH), given to rats with normal functioning parathyroid
glands, led to osteosarcomas in some experimental animals (19,
20). This resulted in a warning against the use of PTH 1–34 in
children. This heightened risk associated with rhPTH administration however, is generally viewed as particular to the rat and
not relevant to PTH-deficient patients receiving physiological
replacement doses.
There are few published studies on the effects of PTH 1–34 in
hypoparathyroidism. In 1990, Strogmann et al. (21) described
the short-term sc PTH 1–38 treatment of two children with hypoparathyroidism. In a randomized controlled trial of 10 adults
lasting 20 wk, we compared conventional therapy, calcitriol and
calcium, with once-daily replacement PTH 1–34 (1). We found
once-daily PTH 1–34 to be superior to calcitriol in the treatment
of hypoparathyroidism because it produced a significantly reduced level of urine calcium excretion and maintained mean
serum calcium levels in the normal range throughout most of the
day. We subsequently performed a randomized cross-over trial
in 17 adults (2) comparing once-daily and twice-daily PTH 1–34
regimens, and found that twice-daily PTH 1–34 allowed a
marked reduction in the total daily PTH 1–34 dose, with less
fluctuation in serum calcium, normalization of urine calcium,
and significantly improved metabolic control. In a subsequent
long-term treatment study, 27 adults with hypoparathyroidism
were randomized to either calcitriol or PTH 1–34 therapy (3).
Our findings demonstrate that twice-daily PTH 1–34 administration maintains serum calcium in the low-normal or just below
the normal range over a 3-yr period with concurrent normalization of urinary calcium excretion. The present study represents
the first randomized controlled trial of PTH 1–34 replacement
therapy in children with hypoparathyroidism. The results
showed, as in the previous study of adult patients with hypoparathyroidism, that a twice-daily regimen produced significantly improved metabolic control compared with once-daily
PTH 1–34 (2).
J Clin Endocrinol Metab, September 2008, 93(9):3389 –3395
Nephrocalcinosis
CT results
PTH Treatment of Hypoparathyroidism
Age
(yr)
Winer et al.
TABLE 1. Clinical and laboratory features of 14 children with hypoparathyroidism at study entry
3390
J Clin Endocrinol Metab, September 2008, 93(9):3389 –3395
Patients were excluded if they had severe renal insufficiency (glomerular
filtration rate ⬍ 25 ml/min) or evidence of liver disease. Creatinine clearance values were corrected for body surface area (Table 1). With the
exception of one patient (A) who received 1-␣-hydroxycholecalciferol
(1-␣ calcidiol), all patients were receiving calcitriol and calcium supplementation at study entry. The duration of hypoparathyroidism at study
entry ranged from 1–11 yr (Table 1). The last calcitriol dose was given
approximately 12 h before the initiation of PTH 1–34. At study entry,
only two subjects (A and K) were receiving magnesium replacement
for treatment of chronic hypomagnesemia (normal range: 0.75–1.00
mmol/liter). Three other patients had magnesium levels below the normal range during the baseline evaluation and were started on magnesium
shortly after study entry. Five subjects developed low-serum magnesium
levels further into the protocol while on PTH 1–34. By the end of the
initial 14-wk period, seven patients were supplemented with magnesium
to maintain fasting serum magnesium levels in the normal range. By the
end of the study, a total of 10 subjects required magnesium supplementation (120 –580 mg/d). Four patients had evidence of nephrocalcinosis
by renal computed tomography scan, and three patients had renal insufficiency (creatinine clearance ⬍ 80 ml/min, corrected for body surface
area). Patient A had a sporadic activating mutation in the calcium-sensing receptor, causing severe hypocalcemia and seizures during infancy
(22). Patients B, C, and G were three brothers in a family containing seven
members (five sons, father, and uncle) with hypoparathyroidism. Subjects H, I, and J were three siblings from a family with no affected parent
or grandparent. Two families (subjects D and E are brothers, and K and
L are brothers), with no prior history of hypoparathyroidism, each had
two affected boys with autoimmune polyglandular failure syndrome
type 1 (APS-1). Patient M’s father and grandmother also had hypoparathyroidism. All patients with idiopathic familial hypoparathyroidism
were tested for the presence of a calcium receptor mutation. A defect was
found in only one patient (A).
Protocol
The study was approved by the institutional review board of the
National Institute of Child Health and Human Development, and all
subjects and their parents gave written informed consent. This was a
randomized, cross-over study comparing once-daily with twice-daily
PTH 1–34 therapy. Randomization to the dose schedules, once-daily or
twice-daily PTH, occurred at the initial baseline study visit. The two
arms, each lasting 14 wk, were divided into a 2-wk inpatient dose-adjustment phase and a 12-wk outpatient phase during which continued
dose adjustment was permitted as indicated. Crossover to the opposite
dose schedule arm occurred at the 14-wk time point.
After completion of baseline testing, study participants were assigned
randomly to receive initially either once-daily PTH 1–34 at 0900 h or
twice-daily PTH 1–34 at 0900 and 2100 h. The PTH 1–34 was administered sc in the extremities with an insulin syringe, and the initial dose
was 0.7 ␮g/kg䡠d for both treatment arms. Synthetic human PTH 1–34
(purchased from Bachem Inc., Torrance, CA) was prepared at the National Institutes of Health Clinical Center for human administration as
previously described (1).
The dose of PTH 1–34 was adjusted in increments or decrements of
approximately 15% to maintain urine calcium within the normal range.
Serum calcium was maintained in the low-normal or just below the
normal range to avoid an increase in urine calcium. Both serum calcium
and 24-h urine calcium were measured daily during the initial 2 wk, and
weekly thereafter.
Dietary intake of calcium ranged from 800 to 1500 mg elemental
calcium during both the inpatient phase (based upon daily dietary calcium intake counts) and outpatient phase (based upon dietary history
and results of a food frequency questionnaire). No study participant
received phosphate binders, diuretics, or other study medications that
affected serum calcium, magnesium, or phosphorus levels.
Study end points
The primary outcome measures were the levels of calcium, phosphorus, and magnesium in the serum and urine. These were assessed in two
jcem.endojournals.org
3391
ways: fasting 0800-h serum calcium, phosphorus, magnesium, and vitamin D levels (before the morning dose of PTH 1–34), along with the
corresponding 24-h urine calcium, phosphorus, and magnesium levels,
were measured six times between wk 12 and 14. The mean (⫾SEM) of
these six measurements is referred to as the 14-wk level. Second, at 14 wk,
near the conclusion of each treatment arm, patients underwent blood
sampling over a 24-h period to assess the time course of PTH 1–34 effects
on mineral metabolism. Serum was collected at 0900 h (before the dose
of PTH 1–34) representing time zero (Fig. 1) and then every 2 h until
0900 h the next morning. On the same day, urine was collected at 4-h
intervals from 0900 h (before PTH 1–34) to 0900 h the next morning.
Subjects consumed a diet containing at least 800 mg elemental calcium
during the 24-h test.
The secondary outcome measures were the dose of PTH 1–34
administered, the serum alkaline phosphatase and osteocalcin, which
reflect bone formation, measured before the morning dose of PTH
1–34, and corresponding 24-h urine pyridinoline and deoxypyridinoline, which reflect bone resorption. Serum 25-hydroxyvitamin D3 and
1,25-hydroxyvitamin D3 were measured at the beginning of each
study arm along with the other serum measures before the morning
PTH 1–34 dose.
Assays
Biochemical assays have been previously described (2). All blood and
urine samples for calcium, phosphorus, magnesium, creatinine, and alkaline phosphatase were measured at the Clinical Center, National Institutes of Health. Blood samples were measured using the Hitachi 917
analyzer (Indianapolis, IN). Urine samples were measured using the
Cobas-Mira analyzer (Montclair, NJ). RIAs for intact PTH 1–34, cAMP,
were measured at Corning Hazleton (Vienna, Va). Vitamin D, total urine
pyridinoline, and deoxypyridinoline and serum osteocalcin, were measured at Quest Diagnostics-Nichols Institute (San Juan Capistrano, CA).
Total urine pyridinoline and deoxypyridinoline were measured by fluorometry after reversed-phase HPLC of hydrolyzed urine.
Statistical analysis
Data are presented as mean ⫾ SD, unless otherwise stated, and were
analyzed using SAS system software version 9.1 (SAS Institute Inc., Cary,
NC). A P value of less than or equal to 0.05 was considered statistically
significant, unless the Bonferroni correction applied. For the analysis of
the 24-h serum and urinary profiles, general linear models for unbalanced designs in repeated measures ANOVA were used due to the additional between- and within-factor of time points during the 24-h period
of testing. Multiple post hoc comparisons were adjusted using the Bonferroni correction. Logarithmic transformation was performed, where
appropriate, to achieve uniformity of variance. The counts of occurrences of hypocalcemia and hypomagnesemia during the 24-h period
were compared using paired t tests. Sequence of treatment had an effect
only on urine phosphorus measures and was adjusted for in the repeated
measures ANOVA.
Results
In this study of children with hypoparathyroidism, we found that
treatment with twice-daily PTH maintained mean serum calcium
values in the normal range throughout the 14-wk treatment
period.
Response to treatment at 14 wk
At the conclusion of the 14-wk treatment arm, the mean total
daily dose on twice-daily PTH 1–34 was significantly lower compared with the once-daily regimen (total twice-daily 25 ⫾ 15
␮g/d vs. once daily 58 ⫾ 28 ␮g/d; P ⬍ 0.001).
3392
Winer et al.
PTH Treatment of Hypoparathyroidism
A
Serum Calcium
2.60
Serum Calcium (mmol/L)
J Clin Endocrinol Metab, September 2008, 93(9):3389 –3395
*
*
2.40
**
*
2.20
*
** *
2.00
1.80
1.60
0
2
4
6
8
10
12
14
16
18
20
22
24
Time (h)
Once-Daily
B
Twice-Daily
Serum Magnesium
Serum Magnesium (mmol/L)
1.20
1.00
0.80
** **
*
14
18
**
0.60
0.40
0
2
4
6
8
10
12
16
20
22
24
Time (h)
Once-Daily
C
Twice-Daily
Serum Phosphorus
Serum calcium, phosphorus, magnesium, vitamin D, alkaline phosphatase, and
osteocalcin mean levels obtained before the
morning dose of PTH 1–34 were repeatedly
measured during the final 2 wk of each treatment arm (Table 2). Twice-daily PTH 1–34
produced significantly higher mean 0800-h
(predose) serum calcium levels compared
with calcium levels on once-daily PTH 1–34
(2.04 ⫾ 0.03 vs. 1.87 ⫾ 0.03 mmol/liter; P ⬍
0.001). Magnesium levels during twicedaily PTH 1–34 were significantly higher
compared with once-daily PTH 1–34
(0.71 ⫾ 0.02 vs. 0.66 ⫾ 0.02 mmol/liter; P ⬍
0.01). By contrast, the 0800-h serum phosphorus values remained elevated during
both dose schedules of PTH 1–34. Markers
of bone formation, alkaline phosphatase,
and osteocalcin increased during PTH 1–34
therapy compared with baseline, but there
was no significant difference between the
two treatment arms. The serum 25-hydroxyvitamin D values were similar during
both dose schedules of PTH 1–34.
The PTH 1–34 dose schedule did not significantly affect mean 24-h urinary mineral
excretion levels. Urine calcium levels were
normal during both treatment arms (5.0 ⫾
1.9 for once-daily vs. 4.6 ⫾ 2.2 mmol/d for
twice-daily PTH 1–34). For both study
arms, the mean urine phosphorus levels
were within normal limits. Mean urine magnesium excretion was similar during once
and twice-daily PTH 1–34. Urine pyridinoline and deoxypyridinoline, markers of
bone turnover, increased in response to PTH
1–34 therapy and were similar during both
PTH 1–34 dose schedules.
2.40
Serum Phosphorus (mmol/L)
2.20
2.00
1.80
1.60
1.40
1.20
1.00
0.80
0.60
0
2
4
6
8
10
12
14
16
18
20
22
24
Time (h)
Once-Daily
Twice-Daily
FIG. 1. Twenty-four hour profile of serum calcium (A), magnesium (B) and phosphorus (C), values (mean ⫾
SD) obtained at 14 wk comparing once vs. twice-daily sc PTH injections given at times zero or 0 and 12 h,
respectively.P ⬍ 0.05 once vs. twice-daily PTH administration.
Twenty-four hour profile of serum
calcium, phosphorus, and magnesium
The 24-h profiles of serum calcium,
phosphorus, and magnesium were measured at the conclusion of each 14-wk
treatment phase (Fig. 1). During the initial
part of the day (2–10 h time points), oncedaily PTH 1–34 produced higher calcium
levels but produced lower levels during the
second part of the day (14 –24 h time
points). Specifically, mean serum calcium
levels were significantly higher at the 6- to
10-h time points in the once-daily arm
(2.44 ⫾ 0.19 mmol/liter for 6 h, 2.31 ⫾
0.19 mmol/liter for 8 h, and 2.17 ⫾ 0.16
mmol/liter for 10 h, P ⫽ 0.02, P ⫽ 0.03,
P ⫽ 0.02, respectively; Fig. 2), whereas
they were significantly lower at the 14- to
J Clin Endocrinol Metab, September 2008, 93(9):3389 –3395
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3393
TABLE 2. Effect of PTH 1–34 regimen on blood and urine mineral levels, markers of bone turnover, and vitamin D levels
measured at 14 wk
Serum
Calcium (mmol/liter)
Phosphorus (mmol/liter)
Magnesium (mmol/liter)
Alkaline phosphatase (U/liter)
25-Hydroxyvitamin D (ng/ml)
1,25 OH vitamin D (pg/ml)
Osteocalcin (ng/dl)
Urine
Calcium (mmol/d)
Phosphorus (mmol/d)
Magnesium (mmol/d)
Pyridinoline (nmol/mmol creatinine)
Deoxypyridinoline (nmol/mmol creatinine)
Baseline calcitriol
Once-daily PTH
Twice-daily PTH
Normal range
2.09 ⫾ 0.06
2.23 ⫾ 0.12
0.77 ⫾ 0.02
207 ⫾ 20.2
32 ⫾ 3.3
31 ⫾ 2.8
14 ⫾ 2.5
1.87 ⫾ 0.03a
2.11 ⫾ 0.05
0.66 ⫾ 0.02a
330 ⫾ 29.4
22 ⫾ 2.5
35 ⫾ 3.2
89 ⫾ 14.7
2.04 ⫾ 0.03
2.08 ⫾ 0.07
0.71 ⫾ 0.02
298 ⫾ 26.4
27 ⫾ 2.2
37 ⫾ 2.6
68 ⫾ 9.3
2.05–2.50
0.8 –1.6
0.65–1.05
100 –320
20 – 80
15– 60
1.6 –9.2
4.6 ⫾ 0.60
22.6 ⫾ 2.24
4.4 ⫾ 0.44
346 ⫾ 23.5
114 ⫾ 8.7
1.25– 6.25
13– 42
3.0 – 4.3
42– 440
17–110
4.7 ⫾ 0.66
19.3 ⫾ 2.84
3.9 ⫾ 0.56
187 ⫾ 15.7
50 ⫾ 4.0
5.0 ⫾ 0.51
21.66 ⫾ 2.38
4.7 ⫾ 0.44
361 ⫾ 26.2
123 ⫾ 10.6
Values are given as means ⫾ SEM. Levels associated with PTH therapy are predose values obtained at the end of a 14-wk treatment arm. Calcitriol treatment was not
optimized in this study or compared with PTH therapy.
a
P ⬍ 0.01 vs. twice-daily PTH.
20-h time points during the second part of the day (1.90 ⫾
0.19 mmol/liter for 14 h,1.87 ⫾ 0.16 mmol/liter for 16 h,
1.87 ⫾ 0.15 mmol/liter for 18 h, and 1.91 ⫾ 0.16 mmol/liter
for 20 h, P ⫽ 0.04, P ⬍ 0.01, P ⬍ 0.01, P ⫽ 0.04, respectively;
Fig. 1). The 24-h mean serum calcium levels were not significantly different overall comparing once- and twice-daily PTH
A
B
Urine Calcium:Creatinine Ratio
2.20
**
**
2.00
1.80
**
1.60
1.40
1.20
1.00
0.80
0.60
0.40
Urine Magnesium:Creatinine Ratio
Urine Calcium:Creatinine Ratio
Urine Magnesium:Creatinine Ratio
1.60
2.40
*
1.40
**
1.20
1.00
0.80
0.60
0.40
0.20
0.20
-4-0
0-4
4-8
8-12
12-16
16-20
20-24
-4-0
0-4
4-8
Once-Daily
C
Once-Daily
Twice-Daily
D
Tubular Phosphorus Reabsorption
7.00
12-16
16-20
20-24
16-20
20-24
Twice-Daily
Urine cAMP
10000
Urine cAMP (nmol/mmol creatinine)
Tubular Phosphorus Reabsorption
8-12
Time (h)
Time (h)
6.00
5.00
4.00
**
1000
**
100
-4-0
0-4
4-8
8-12
12-16
Time (h)
Once-Daily
16-20
20-24
-4-0
0-4
4-8
8-12
12-16
Time (h)
Twice-Daily
Once-Daily
Twice-Daily
FIG. 2. Twenty-four hour profile of urine excretion of mean calcium (A), magesium (B) and phosphorus (C), and cAMP (D) values (mean ⫾ SD) obtained at the
conclusion of each study arm comparing once-daily and twice-daily PTH sc injections at times zero or 0 and 12 h, respectively.P ⬍ 0.05 once vs. twice-daily PTH
administration.
3394
Winer et al.
PTH Treatment of Hypoparathyroidism
1–34 (2.07 ⫾ 0.27 mmol/liter for once-daily vs. 2.11 ⫾ 0.20
mmol/liter for twice-daily; P ⫽ 0.6).
Particularly during the second half of the day (12–24 h),
twice-daily PTH 1–34 normalized serum calcium levels more
effectively than once-daily PTH 1–34. For these children the
frequency of hypocalcemia during the 24-h test was significantly
less during twice-daily PTH 1–34 than during once-daily PTH
1–34 (mean count 2.1 ⫾ 1.3 vs. 4.0 ⫾ 2.4; P ⬍ 0.001). Twicedaily PTH 1–34 produced mean levels of hypocalcemia only
during three time points (0, 10, and 12 h), whereas once-daily
PTH 1–34 produced mean hypocalcemic levels at seven different
time points (0, and 12–24 h) during the 24-h test.
Over the 24-h period, ANOVA demonstrated a statistically
significantly higher level of serum magnesium response to twicedaily PTH 1–34 than once-daily (0.68 ⫾ 0.10 vs. 0.62 ⫾ 0.09;
P ⬍ 0.01). For patients on once-daily therapy, magnesium levels
remained subnormal during the 10- to 24-h time points. Twicedaily PTH 1–34 produced normal mean serum magnesium levels
throughout the day, which were significantly higher for the 14to 18-h and 24-h time points (0.69 ⫾ 0.11 mmol/liter for 14, 16,
and 18 h, and 0.66 ⫾ 0.07 mmol/liter at 24 h, P ⫽ 0.003, P ⫽
0.003, P ⫽ 0.01, P ⫽ 0.008, respectively; Fig. 1).
There were no significant differences in the serum phosphorus response to PTH 1–34 related to the number of doses
of PTH 1–34 administered. In contrast to serum calcium, for
which the greatest difference between the two regimens was
observed during the latter portion of the day, there were no
differences in nighttime phosphorus levels between the two
regimens (Fig. 1). Mean 24-h serum phosphorus levels remained similar and above normal during both the twice-daily
and once-daily regimens (1.92 ⫾ 0.21 mmol/liter vs. 1.83 ⫾
0.26 mmol/liter; P ⫽ 0.1).
Twenty-four hour profile of urine calcium, phosphorus,
magnesium, and cAMP
The 24-h profiles of urine calcium, phosphorus, magnesium,
and cAMP were measured at the conclusion of each 14-wk treatment phase (Fig. 2). Except for tubular phosphorus reabsorption
(P ⫽ 0.03), none of the mean urine profiles was statistically
different by treatment over the 24-h period; however, there were
differences at specific time points for some of these measures.
The mean urine calcium to creatinine ratio was significantly
higher at the 8- to 12-h time point during the once-daily arm
(1.71 ⫾ 0.80 mmol/liter; P ⫽ 0.001), and significantly lower
during the once-daily arm at the 16- to 20-h and 20- to 24-h time
points (0.85 ⫾ 0.47 and 0.84 ⫾ 0.42 mmol/liter; P ⫽ 0.0007, P ⫽
0.009, respectively). During the 8 –12 and 12- to 16-h time
points, once-daily PTH 1–34 produced significantly higher mean
urine magnesium levels than twice-daily PTH 1–34 (1.24 ⫾ 0.63
and 1.02 ⫾ 0.53 mmol/liter; P ⫽ 0.03 and P ⫽ 0.001, respectively). Mean urine phosphorus levels were similar, demonstrating no significant differences in the urine phosphorus response to
PTH 1–34 related to the number of doses administered. The
mean urine cAMP excretion was significantly higher at the 0- to
4-h time point during the once-daily arm (2801.40 ⫾ 2005.12
mmol/liter; P ⫽ 0.001) but lower at the 12–16 h (206.93 ⫾ 50.83
mmol/liter; P ⫽ 0.001).
J Clin Endocrinol Metab, September 2008, 93(9):3389 –3395
Adverse events
Adverse events were similar for both dose regimens. Subjects
continued to experience occasional symptoms of neuromuscular
irritability associated with serum calcium fluctuations. None of
the patients experienced severe hypocalcemia or hypercalcemia
requiring emergency therapy at any time during the study. There
were no episodes of seizures in any of the study patients while
receiving PTH 1–34 therapy. Several study patients continued to
have occasional cramping, numbness, and tingling associated
with transient hypocalcemia. Although conventional therapy
was not compared with PTH 1–34 in this study, several patients
reported an improved quality of life during PTH therapy due to
fewer episodes of severe hypocalcemia. This was most apparent
in the children with APS-1 who experience recurrent hypocalcemia associated with chronic intermittent malabsorption.
Discussion
We have shown, in a randomized-controlled study, the efficacy
of PTH 1–34 in the treatment of hypoparathyroidism in children.
These findings are consistent with our previously reported study
in adults in which we demonstrated that twice-daily PTH 1–34,
at a significantly lower daily dose, provides improved metabolic
control compared with once-daily PTH 1–34 therapy. PTH 1–34
was well tolerated by all subjects during both treatment
regimens.
The benefits of twice-daily PTH 1–34, assessed by the ability
of this dose schedule to maintain normal serum calcium concentrations with simultaneous normalization of urine calcium levels, have been demonstrated here. Some fluctuation of serum
calcium below the normal range still exists toward the end of the
12-h interdose interval. Hypocalcemia, however, was less frequent with twice-daily compared with once-daily PTH 1–34, and
the improved maintenance of normal calcium concentrations,
especially toward the end of the day, underscores the advantage
of twice-daily dosing.
Further refinement of PTH administration may be provided
by three times daily or perhaps by continuous delivery via patch
or pump. This may also improve serum phosphorus and magnesium levels that have been suboptimal on the PTH dose regimens studied here. As in the prior study in adults, serum phosphorus levels remain elevated on PTH 1–34, and the need for
magnesium supplementation appears to increase with PTH 1–34
therapy.
The increase in markers of bone turnover observed in children
was similar to that observed during prior PTH 1–34 treatment
studies in adults (1–3). Chronic elevation of bone turnover markers and the associated increase in skeletal remodeling activity
may cause microscopical bone changes similar to chronic hyperparathyroidism, a disorder associated with decreased bone mineral density. Long-term studies are needed to determine if markers of bone turnover remain elevated and if anabolic effects on
bone mineral density, similar to those observed with PTH treatment of osteoporotic adults (17, 18, 23), also apply to children
with hypoparathyroidism. This is especially important in light of
the warning against the use in children of rhPTH (Forteo; Eli Lilly
J Clin Endocrinol Metab, September 2008, 93(9):3389 –3395
& Co., Indianapolis, IN) because of a potentially heightened risk
of osteosarcoma.
PTH 1–34 is not compared with calcitriol in this study. Accordingly, it remains unknown whether PTH 1–34 is a superior
treatment for hypoparathyroidism in children. Further studies to
compare conventional therapy to parathyroid replacement in
children are needed. Comparing two dose schedules of PTH1–34
administration, our data demonstrate that replacement therapy
with twice-daily dosing is more physiological. Once-daily PTH
1–34 appeared to have diminishing effects toward the end of the
day, thus producing subnormal calcium and magnesium levels.
During the twice-daily arm, mean serum calcium and magnesium
levels were higher during the final 10 h of the day. We conclude
that a twice-daily PTH 1–34 regimen provides a more effective
treatment of hypoparathyroidism compared with once-daily
treatment in children because it reduces the variation in serum
calcium levels at a lower total daily PTH 1–34 dose. Further
studies are needed to determine the long-term efficacy and
safety of twice-daily PTH 1–34 replacement in children with
hypoparathyroidism.
jcem.endojournals.org
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
Acknowledgments
We thank the National Institutes of Health Clinical Center fellows and
nursing staff for their contributions and support. We also thank nutritionist Nancy Sebring for her contributions.
15.
16.
Address all correspondence and requests for reprints to: Karen K.
Winer, M.D., National Institutes of Health, National Institute of Child
Health and Human Development/Center for Research for Mothers &
Children/Endocrinology, Nutrition,and Growth Branch, Building 6100,
Room 4B11, Bethesda, Maryland 20892-7510. E-mail: winerk@mail.
nih.gov.
Present address for G.B.C.: Eli Lilly & Co., Indianapolis, Indiana
46285-0520. Present address for B.S.: University of Illinois, Chicago, IL
60612-7323.
Disclosure Statement: K.K.W., N.S., D.P., and B.S. have nothing to
disclose. G.B.C. is currently employed by Eli Lilly & Co.
17.
18.
19.
20.
References
21.
1. Winer KK, Yanovski JA, Cutler GB 1996 Synthetic human parathyroid hormone 1–34 vs calcitriol and calcium in the treatment of hypoparathyroidism.
JAMA 276:631– 636
2. Winer KK, Yanovski JA, Sarani B, Cutler GB 1998 A randomized, cross-over
trial of once-daily versus twice-daily parathyroid hormone 1–34 in treatment
of hypoparathyroidism. J Clin Endocrinol Metab 83: 3480 –3486
3. Winer KK, Ko CW, Reynolds J, Dowdy K, Keil M, Peterson D Gerber L,
McGarvey C, Cutler GB 2003 Long-term treatment of hypoparathyroidism: a
randomized controlled study comparing parathyroid hormone-(1–34) versus
calcitriol and calcium. J Clin Endocrinol Metab 88:4214 – 4220
4. Chan JC, Young RB, Alon U, Mamunes P 1983 Hypercalcemia in children
22.
23.
3395
with disorders of calcium and phosphate metabolism during long-term treatment with 1,25-dihydroxyvitamin-D3. Pediatrics 72:225–233
Chan JC, Young RB, Hartenberg MA, Chinchilli VM 1985 Calcium and phosphate metabolism in children with idiopathic hypoparathyroidism or
pseudohypoparathyroidism: effects of 1,25-dihydroxyvitamin D3. J Pediatr
106:421– 426
Christiansen C, Rodbro P, Christensen MS, Hartnack B 1978 Deterioration of
renal function during the treatment of chronic renal failure with 1,25 dihydroxycholecalciferol. Lancet 2:700 –703
Davies M 1989 High-dose vitamin D therapy: indications, benefits and hazards. Int J Vitam Nutr Res Suppl 30:81– 86
Kurokawa K 1987 Calcium-regulating hormones and the kidney. Kidney Int
32:760 –771
Markowitz ME, Rosen JF, Smith C, DeLuca HF 1982 1,25-dihydroxyvitamin
D3-treated hypoparathyroidism: 35 patients years in 10 children. J Clin Endocrinol Metab 55:727–733
Santos F, Smith MJ, Chan JC 1986 Hypercalciuria associated with long-term
administration of calcitriol (1,25-dihydroxyvitamin D3). Action of hydrochlorothiazide. Am J Dis Child 140:139 –142
Weber G, Cazzuffi MA, Frisone F, de Angelis M, Pasolini D, Tomaselli V,
Chiumello G 1988 Nephrocalcinosis in children and adolescents: sonographic
evaluation during long-term treatment with 1,25-dihydroxycholecalciferol.
Child Nephrol Urol 9:273–276
Allen SH, Shah JH 1992 Calcinosis and metastatic calcification due to vitamin
D intoxication. Horm Res 37:68 –77
Litvak J, Moldawer MP, Forbes AP, Henneman PH 1958 Hypocalcemic hypercalciuria during vitamin D and dihydrotachysterol therapy of hypoparathyroidism. J Clin Endocrinol Metab 18:246 –252
Winer KK, Ko CW, Kopp JB 2004 Iatrogenic nephrocalcinosis and renal failure in two family members with treated hypoparathyroidism due to a calciumsensing receptor mutation. Clinical Cases in Mineral and Bone Metabolism
1:129 –132
Slovik DM, Neer RM, Potts JT 1981 Short-term effects of synthetic human
parathyroid hormone 1–34 administration on bone mineral metabolism in
osteoporotic patients. J Clin Invest 68:1261–1271
Slovik DM, Rosenthal DI, Doppelt SH, Potts Jr JT, Daly MA, Campbell JA,
Neer RM 1986 Restoration of spinal bone in osteoporotic men by treatment
with parathyroid hormone 1–34 and 1,25 dihydroxyvitamin D. J Bone Miner
Res 1:377–381
Finkelstein JS, Kibanski A, Schaefer EH, Hornstein MD, Schiff I, Neer RM
1994 Parathyroid hormone for the prevention of bone loss induced by estrogen
deficiency. N Engl J Med 331:1618 –1623
Neer RM, Arnaud JR, Zanchetta R, Prince R, Gaich GA, Reginster JY,
Hodsman AB, Genant HK, Wang O, Mitlk BH 2001 Effect of parathyroid
hormone 1–34 on fractures and bone mineral density in postmenopausal
women with osteoporosis. N Engl J Med 344:1434 –1441
Vahle JL, Long GG, Sandusky G, Westmore M, Ma YL, Sato M 2004 Bone
neoplasms in F344 rats given teriparatide [rhPTH(1–34)] are dependent on
duration of treatment and dose. Toxicol Pathol 32:426 – 438
Sato M, Ma YL, Hock JM, Westmore MS, Vahle J, Villanueva A, Turner CH
2002 Skeletal efficacy with parathyroid hormone in rats was not entirely beneficial with long-term treatment. J Pharmacol Exp Ther 302:304 –313
Strogmann W, Bohrn E, Woloszezuk W 1990 [Initial experiences with substitution treatment of hypoparathyroidism with synthetic human parathyroid
hormone]. Monatsschr Kinderheilkd 138:141–146 (German)
Baron J, Winer KK, Yanovski J, Cunningham A, Laue L, Zimmerman D,
Cutler GB 1996 Mutations in the Ca-sensing receptor gene cause autosomal
dominant and sporadic hypoparathyroidism. Hum Mol Genet 5:601– 606
Misof BM, Roschger P, Cosman F, Kurland ES, Tesch W, Messmer P,
Dempster DW, Nieves J, Shane E, Fratzl P, Klaushofer K, Bilezikian J,
Lindsay R 2003 Effects of intermittent parathyroid hormone administration on bone mineralization density in iliac crest biopsies from patients with
osteoporosis: a paired study before and after treatment. J Clin Endocrinol
Metab 88:1150 –1156