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Original Studies |
Developmental Endocrinology Branch, National Institutes of Health, Bethesda, Maryland 20892-1862
Address all correspondence and requests for reprints to: Karen K. Winer, National Institute of Child Health and Human Development/Developmental Endocrinology Branch, Building 10, Room 10N262, 10 Center Drive, MSC 1862, National Institutes of Health, Bethesda, Maryland 20892-1862.
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Abstract |
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During the second half of the day (12–24 h), twice-daily PTH increased serum calcium and magnesium levels more effectively than once-daily PTH. In patients with calcium receptor mutations (CaR), once-daily PTH normalized urine calcium, provided that serum calcium was maintained at levels below normal range. However, twice-daily PTH treatment produced higher mean serum calcium in patients with CaR with no significant rise in urine calcium excretion, and with no significant differences in either serum or urine calcium levels between CaR and patients with acquired or idiopathic hypoparathyroidism. Thus, treatment with twice-daily PTH is the better regimen for patients with CaR to overcome their tendency to hypercalciuria while producing near-normal levels of serum calcium. The total daily PTH dose was markedly reduced with the twice-daily regimen (twice daily 46 ± 52 vs. once daily 97 ± 60 µg/day, P < 0.001). We conclude that a twice-daily PTH regimen provides effective treatment of hypoparathyroidism and reduces the variation in serum calcium levels at a lower total daily PTH dose.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Synthetic human PTH 1–34 was initially administered to humans as a treatment for osteoporosis (11, 12, 13). We have recently found that once-daily sc injections of PTH may be superior to calcitriol in the treatment of hypoparathyroidism (14). Once-daily PTH therapy significantly reduced the level of urine calcium excretion compared with calcitriol therapy and maintained serum calcium in the normal range throughout most of the day. Some patients, however, had periods of hypocalcemia near the end of the 24-h period.
We hypothesized that twice-daily administration of lower doses of PTH would improve the 24-h serum calcium profile and would continue to maintain urine calcium excretion within the normal range. To test this hypothesis, we performed a randomized cross-over trial, comparing once-daily and twice-daily PTH regimens in 17 adult patients with hypoparathyroidism. We found that twice-daily PTH allowed for a marked reduction in the total daily PTH dose, with less fluctuation in serum calcium, normalization of urine calcium, and significantly improved metabolic control in patients with calcium receptor mutations (CaR).
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Seventeen adult subjects, ages 19–64 yr, with
hypoparathyroidism were studied (Table 1
). These study subjects did not
participate in a previous pilot study comparing PTH with calcitriol in
the treatment of hypoparathyroidism (14). The diagnosis of
hypoparathyroidism was determined in each subject by low levels of
intact PTH during hypocalcemia (data not shown). Four patients (E-H)
were from a single family of autosomal dominant hypoparathyroidism in
which we identified a calcium receptor mutation (15). Patient J
had a sporadic mutation in the calcium receptor causing severe
hypocalcemia and seizures during infancy (16). All patients were
receiving calcitriol and calcium supplementation at study entry.
Patients who were managed with other vitamin D analogs before the study
were switched to calcitriol at least 1 month before study entry. All
study patients had received vitamin D and calcium supplementation for
at least 3 yr. There was no drug-free interval before starting the
protocol, and the last vitamin D dose was given approximately 12 h
before the initiation of PTH. Only 5 subjects were receiving magnesium
replacement (130–450 mg/day) at study entry. Two other patients had
low-normal magnesium levels at baseline, and later had low serum
magnesium levels while on PTH. By the end of the initial 14-week
period, 11 patients were supplemented with magnesium (100–600 mg/day).
All 5 patients with CaR required magnesium supplementation. Eight
patients had evidence of nephrocalcinosis by renal computerized
tomography scan, and 14 patients (80%) had renal insufficiency (Table 1).
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The study was approved by the Institutional Review Board of the National Institute of Child Health and Human Development (NICHD). Informed consent was obtained from all subjects. A randomized, cross-over design was used to compare once-daily PTH with twice-daily PTH therapy. The two arms, each lasting 14 weeks, were divided into a 2-week inpatient dose-adjustment phase and a 12-week outpatient phase during which continued dose adjustment was permitted as indicated.
PTH was administered sc (in the extremities with an insulin syringe) once daily at 0900 h or twice daily at 0900 h and 2100 h. The initial dose was 0.7 µg/kg per day for both treatment arms. The dose of PTH was adjusted in increments or decrements of approximately 5–10% to maintain urine and serum calcium within the normal range. For several patients it was necessary to maintain the serum calcium below the normal range to obtain normal urine calcium excretion. Both serum calcium and 24-h urine calcium were measured daily during the initial 2 weeks and weekly thereafter.
Dietary intake of calcium ranged from 1–2 g of elemental calcium during both the inpatient phase (based on daily dietary calcium intake counts) and outpatient phase (based on dietary history). One subject received oral calcium supplementation when her dietary calcium remained below 800 mg/day because of lactose intolerance. This subject was given sufficient calcium supplementation to raise her total elemental calcium intake to 1000 mg/day. No study participant received phosphate binders, diuretics, or other study medications that affected serum calcium, magnesium, or phosphorus levels.
The primary outcome measures were the levels of calcium, phosphorus, and magnesium in serum and urine. These were assessed in two ways. First, 0800 h serum calcium, phosphorus, and magnesium levels (before the morning dose of PTH), along with the corresponding 24-h urine calcium, phosphorus, and magnesium levels, were measured six times between weeks 12 and 14. The mean of these six measurements is referred to as the 14-week level. Second, at 14 weeks, near the conclusion of each treatment arm, patients underwent blood sampling over a 24-h period to assess the time course of PTH effects on mineral metabolism. Serum was collected at 0900 h (before the dose of PTH) 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) to 0900 h the next morning. Subjects consumed a diet containing at least 1000 mg of elemental calcium during the 24-h test.
The secondary outcome measures were the dose of PTH administered, the serum alkaline phosphatase and osteocalcin (which reflect bone formation) measured before the morning dose of PTH, and corresponding 24-h urine pyridinoline and deoxypyridinoline (which reflect bone resorption). Serum 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 were measured at the beginning of each study arm along with the other serum measures before the morning PTH dose.
Preparation of PTH
Lyophilized human PTH 1–34 was purchased from Bachem California, Inc. (Torrance, CA) and prepared for human administration as previously described (14).
Biochemical assays
All blood and urine samples for calcium, phosphorus, magnesium, creatinine, and alkaline phosphatase were measured at the Clinical Center, NIH. Blood samples were measured using the Hitachi Scientific Instruments, Inc. 917 analyzer (Indianapolis, IN). Urine samples were measured using the Cobas-Mira analyzer (Montclair, NJ). RIAs for intact PTH (17), cAMP, and vitamin D (18), were measured at Corning Hazleton (Vienna, VA), and total urine pyridinoline and deoxypyridinoline and serum osteocalcin (19), were measured at Corning-Nichols Institute Diagnostics (San Juan Capistrano, CA). Total urine pyridinoline and deoxypyridinoline were measured by flurometry after reversed-phase high performance liquid chromatography of hydrolyzed urine (20).
Statistical analysis
Data are presented as mean ± SD unless
otherwise stated. Data from the two arms of the study were compared by
repeated measures of ANOVA, with Bonferroni’s adjustment applied to
correct for the number of ANOVAs performed. The sequence of the dose
regimens and the etiology of the hypoparathyroidism were the two
between-group factors in all ANOVAs. Patients were divided into those
with calcium receptor defects and those with any other etiology for
hypoparathyroidism (idiopathic and postsurgical hypoparathyroidism).
Post hoc comparisons at individual time points were
performed with paired and unpaired Fisher’s protected least
significant difference tests. Contingency table analysis was applied to
categorical data. Logarithmic transformation was performed, where
appropriate, to achieve uniformity of variance. There were no sequence
effects on urine or serum calcium and phosphorus levels (data not
shown). Because the baseline results in Table 2 were obtained while most patients were
receiving the calcitriol regimen prescribed by their referring
physician, no statistical comparisons were made to these data because
the calcitriol treatment regimens had not been optimized.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Serum calcium, phosphorus, magnesium, vitamin D, and alkaline
phosphatase levels obtained before the morning dose of PTH were
repeatedly measured during the final 2 weeks of each treatment arm, and
the means of these values are given in Table 2
. Patients with CaR had
significantly lower mean 0800 h serum calcium levels during
once-daily PTH compared with patients with other etiologies of
hypoparathyroidism (1.67 ± 0.12 vs. 2.02 ± 0.18
mmol/L, P < 0.001). The mean 0800 h serum calcium
was significantly higher in CaR patients receiving twice-daily
compared with once-daily PTH (1.91 ± 0.15 vs.
1.67 ± 0.12 mmol/L, P < 0.02). By contrast, the
0800 h calcium values were equally well maintained during both
dose schedules of PTH for patients with idiopathic or postsurgical
hypoparathyroidism. Serum magnesium was significantly greater for all
study patients on twice-daily PTH compared with once-daily PTH
(0.68 ± 0.08 vs. 0.64 ± 0.07 mmol/L,
P < 0.008). The serum phosphorus values were equally
well maintained during both dose schedules of PTH.
Patients with CaR defects had similar levels of alkaline phosphatase compared with patients with other etiologies of hypoparathyroidism on both dosage regimens. Although mean serum alkaline phosphatase was lower during twice-daily compared with once-daily PTH therapy (146 ± 51 vs. 243 ± 272 U/L, P < 0.05) for all subjects, this difference appeared to be related to an order effect. Patients receiving daily PTH during the second treatment arm, after receiving twice daily PTH, had significantly greater elevations in alkaline phosphatase levels compared with patients receiving daily PTH in the initial 3 months of the study. This order effect was not apparent for twice-daily PTH. Mean serum osteocalcin, 25-hydroxyvitamin D3, and 1,25 dihydroxyvitamin D3 levels were similar during both study arms for all etiologies of hypoparathyroidism.
As we have previously reported (14), PTH reduced the level of mean
urine calcium excretion for all subjects compared with baseline levels
on calcitriol therapy (Table 2). The PTH dose schedule did not
significantly affect mean 24-h urinary calcium and phosphorus excretion
levels. For both study arms, mean urine calcium levels were within the
normal range for the 13 female subjects. However, mean urine calcium
excretion was above normal in the 4 male subjects during both study
arms. Although patients with CaR and other etiologies of
hypoparathyriodism had similar urine magnesium excretion, mean urine
magnesium excretion for all subjects was significantly lower during
twice-daily PTH (4.8 ± 1.90 vs. 5.3 ± 2.0
mmol/24h, P < 0.01), although still above the normal
range. Urine pyridinoline and deoxypyridinoline, markers of bone
turnover, were similar during both dose schedules.
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-week treatment phase (Fig. 1). ANOVA demonstrated significant
differences in the serum calcium response to PTH related to the
etiology of hypoparathyroidism (P < 0.002) and related
to the number of doses of PTH administered (P <
0.0001). The 24-h mean serum calcium level in patients with CaR
compared with patients with other etiologies of hypoparathyroidism
showed a significantly lower mean serum calcium level during the
once-daily arm (1.8 ± 0.16 mmol/L for CaR and 2.13 ± 0.11
mmol/L for others; Fig. 1, P < 0.0002). The 24-h mean
serum calcium level in patients with CaR compared with others was not
significantly different during the twice-daily arm (1.96 ± 0.15
mmol/L for CaR and 2.10 ± 0.17 mmol/L for others; Fig. 1, P = 0.16).
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ANOVA demonstrated significant differences in the serum magnesium
response to PTH related to the number of doses of PTH administered
(P < 0.003). For patients with CaR, magnesium levels
remained subnormal during both treatment arms. For patients with
acquired and idiopathic hypoparathyroidism, twice-daily PTH produced
normal serum magnesium levels throughout the day. During the
twice-daily arm, mean serum magnesium levels were significantly higher
during the final 8 h of the day (16–24 h) for patients with
acquired and idiopathic hypoparathyroidism (Fig. 1). Once-daily PTH,
however, appeared to have diminishing effects toward the end of the
day, thus producing subnormal magnesium levels.
Mean 24-h serum phosphorus levels remained supranormal during both the
twice- and once-daily regimens (1.42 ± 0.20 mmol/L vs.
1.45 ± 0.15 mmol/L, P = 0.34). Mean 24-h
phosphorus levels did not differ for patients with CaR compared with
other causes of hypoparathyroidism (P = 0.26). However,
there were significant differences in the serum phosphorus response to
PTH related to the number of doses of PTH administered
(P < 0.02). In contrast to serum calcium, for which
the greatest difference in patients with CaR 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).
Twenty four-hour profile of urine calcium, phosphorus, magnesium, and cAMP
Twice-daily PTH produced a bimodal 24-h urine profile for urine
calcium, magnesium, phosphorus, and cAMP, whereas once-daily PTH
produced a unimodal profile (P < 0.001 by ANOVA; Fig. 2). For patients with CaR, urine calcium
levels were significantly higher during twice-daily PTH than the
once-daily arm during most of the latter portion of the day
(P < 0.01, 12–16 h and 16–20 h). For patients with
idiopathic and postsurgical hypoparathyroidism, twice-daily PTH
produced urine calcium levels significantly lower than levels on
once-daily PTH during the middle portion of the day (P
< 0.05, 8–12 h, 12–16 h), but significantly higher than once-daily
PTH from 16–20 h (P < 0.05).
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The tubular reabsorption of phosphorus decreased in response to PTH within the first 4 h of PTH administration. When patients received twice-daily PTH, tubular phosphorous reabsorption was significantly lower during most of the latter portion of the day (P < 0.04, 12–16 h for CaR; P < 0.01, 12–16 h, 16–20 h for acquired and idiopathic). Urine cAMP levels rose in response to PTH administration on both dose schedules and peaked at 4–8 h after PTH administration.
PTH dose
The total daily PTH dose required to maintain serum calcium in the
normal or near normal range was significantly lower for all subjects
receiving twice-daily PTH (46 ± 32 µg/day) than once daily PTH
(97 ± 60 µg/day, P < 0.001, Table 2). After 14
weeks of treatment, the PTH dose administered to individual subjects
ranged from 0.07–1.84 µg/kg per day (mean 0.62 ± 0.45 µg/kg
per day) during the twice-daily arm and 0.14–4.20 µg/kg per day
(mean 1.48 ± 1.29 µg/kg per day) during the once-daily arm.
During the once-daily PTH arm, individuals with CaR required
significantly more PTH per kilogram body weight (2.62 ± 1.58
µg/kg per day) compared with patients with other etiologies of
hypoparathyroidism (1.00 ± 0.81 µg/kg per day,
P < 0.05). For patients who received magnesium
supplementation, the dose of elemental magnesium was similar during
both treatment arms.
Adverse events
In this open, unblinded, pilot study, bone pain (tibial discomfort) was reported in four patients during the once-daily arm and in one patient during the twice-daily arm (P = not significant). On three occasions, one patient developed nausea within 4 h of his single-daily PTH injection, whereas no nausea was reported during twice-daily PTH. Two patients had nocturia during twice-daily PTH therapy, which was not observed during the once-daily arm. Two patients complained of fatigue during the once-daily arm, whereas there were no complaints of fatigue during twice-daily therapy. Twelve out of the 17 patients preferred twice-daily over daily PTH despite the inconvenience of the second injection (P < 0.05).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Serum phosphorus levels normally follow a diurnal variation, with higher levels at night. This rhythm persisted during both dose schedules and was not affected by the second dose of PTH in the evening. We encouraged the patients to eat dairy products, which are high in both phosphorus and calcium. We hypothesize that it might be possible to achieve lower phosphorus levels by eliminating dairy products and supplementing the diet with calcium.
All protocol patients with CaR had magnesium deficiency and required supplementation. Individuals with a gain of function mutation in the calcium receptor may have a greater tendency to hypomagnesemia, because this receptor, in part, controls magnesium reabsorption in the kidney (21). This might reflect reduced magnesium tubular reabsorption, which may increase the tendency toward hypomagnesemia in this form of hypoparathyroidism. In addition, the overall increased need for magnesium supplementation in the group with other etiologies for hypoparathyroidism may be because of a referral bias or due to the closer monitoring and higher attentiveness to this issue on the part of the investigators.
Previously reported data on the pharmacokinetics of PTH 1–34 have demonstrated maximal serum levels 30 min after sc injection in osteoporotic subjects (22). N-terminal PTH levels measured in hypoparathyroid patients from our previous study (our unpublished data) showed mean peak levels at 40 min after sc PTH injection (14). We also reported that circulating levels of 1,25 dihydroxyvitamin D peaked 8 h after PTH administration. Although these measures were not repeated in the present study group, one can assume a similar response. It is interesting to note that serum calcium levels rise approximately 3 h after the expected time of peak serum PTH level and 4 h before the maximal serum vitamin D level. The rise in serum calcium after PTH administration results from a 2-fold response. First, a rapid direct response at the level of the kidney to decrease calcium clearance and second, a more prolonged effect of endogenous calcitriol on the gastrointestinal tract to increase calcium absorption. We do not know whether mobilization of calcium from the bone contributes to the rise in serum calcium in response to PTH, because markers of bone turnover were not included in the 24-h serum profile.
The experimental design was not conducive to effectively measuring changes in bone in response to these two dose regimens. The relatively brief 14-week time period does not provide sufficient time to observe trends that might reflect the potential for long-term effects of these two dose regimens on the bone. Based on our experience, the decreased incidence of bone pain, the decrease in the levels of bone turnover markers during the twice-daily regimen, and the decreased incidence of hypercalcemia during twice-daily PTH, we hypothesize that twice-daily PTH is more physiological for the bone. There have been no clinical studies exploring the effect of multiple daily doses of PTH 1–34 on bone in humans with hypoparathyroidism. There are, however, animal studies that support our hypothesis that a shorter interval between doses of PTH 1–34 enhances the anabolic response in bone despite the administration of smaller doses (23). Numerous studies have shown that intermittent administration of PTH is more anabolic for the bone compared with continuous infusion of PTH (24, 25).
Nocturia, a side effect that appeared to differ according to the dose schedule, may have occurred more frequently during twice-daily PTH because of the relatively higher nighttime urine calcium levels during that treatment arm. Additionally, PTH is known to have natriuretic effects, which may explain nocturia after the second PTH dose. Although this adverse effect might be reduced by a different dose fractionation, such as giving 40% of the daily dose at night and 60% in the morning, this possibility has not yet been examined.
The total daily PTH dose required to maintain serum calcium in the normal or near-normal range was reduced by nearly 50% with twice-daily PTH. Patients with mild renal insufficiency might be expected to need more PTH than those with normal renal function (26). This does not appear to be the case in our study. The subject (F) with the lowest glomerular filtration rate (GFR) required similar doses during once-daily PTH (3.4 µg/kg per day) compared with subject B with normal GFR and malabsorption. Subject F, however, required higher doses during twice-daily PTH (0.95 µg/kg per day) compared with subject B (0.66 µg/kg per day). Another example, subject (E) with a GFR of 45 mL/min, required PTH doses of 4.2 µg/kg per day during once-daily PTH and 1.8 µg/kg per day during twice daily PTH. Her mother, (subject G) whose GFR was significantly worse (29 mL/min), required much lower doses: 0.7 µg/kg per day during once-daily PTH and 0.4 µg/kg per day during the twice daily PTH arm. Although renal function may be a contributing factor, gastrointestinal absorption of calcium may also be an important factor determining individual PTH requirements.
In conclusion, twice-daily PTH provides effective short-term treatment for hypoparathyroidism, with a markedly reduced total PTH dose, an apparent reduction in bone turnover, and a decreased incidence of bone pain compared with a once-daily regimen. Unresolved issues include the long-term effects of PTH therapy on bone density, renal complications, and the possible emergence of resistance to PTH. To address these longer term issues, we are currently conducting a randomized parallel study to compare the long-term outcome of PTH and calcitriol (both given twice daily) in the treatment of chronic hypoparathyroidism.
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Acknowledgments |
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Footnotes |
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Received July 14, 1997.
Revised May 28, 1998.
Accepted July 2, 1998.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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). Shaded
region indicates normal range. PTH was administered at 0 h
(0900 h) or 0 and 12 h, during once- and twice-daily arms,
respectively. *, P < 0.05; **,
P < 0.01 twice- vs. once-daily PTH
treatment.