ORIGINAL
ARTICLE
E n d o c r i n e
C a r e
Therapy of Hypoparathyroidism with PTH(1– 84):
A Prospective Four-Year Investigation of Efficacy
and Safety
Natalie E. Cusano, Mishaela R. Rubin, Donald J. McMahon, Chiyuan Zhang,
Rebecca Ives, Amanda Tulley, James Sliney Jr., Serge C. Cremers,
and John P. Bilezikian
Department of Medicine, Division of Endocrinology, College of Physicians and Surgeons, Columbia
University, New York, New York 10032
Context: PTH may be an effective treatment option for hypoparathyroidism, but long-term data
are not available.
Objective: We studied the effect of 4 yr of PTH(1– 84) treatment in hypoparathyroidism.
Design: Twenty-seven subjects were treated with PTH(1– 84) for 4 yr, with prospective monitoring
of calcium and vitamin D requirements, serum and urinary calcium, serum phosphorus, bone
turnover markers, and bone mineral density (BMD).
Results: Treatment with PTH(1– 84) reduced supplemental calcium requirements by 37% (P ⫽ 0.006)
and 1,25-dihydroxyvitamin D requirements by 45% (P ⫽ 0.008). Seven subjects (26%) were able to stop
1,25-dihydroxyvitamin D completely. Serum calcium concentration remained stable, and urinary calcium and phosphorus excretion fell. Lumbar spine BMD increased by 5.5 ⫾ 9% at 4 yr (P ⬍ 0.0001).
Femoral neck and total hip BMD remained stable. At 4 yr, distal radius BMD was not different from
baseline. Bone turnover markers increased significantly, reaching a 3-fold peak from baseline values at
6 –12 months (P ⬍ 0.05 for all), subsequently declining to steady-state levels at 30 months. Hypercalcemia was uncommon (11 episodes in eight subjects over 4 yr; 1.9% of all values), with most episodes
occurring within the first 6 months and resolving with adjustment of supplemental calcium and vitamin D.
Conclusions: PTH(1– 84) treatment of hypoparathyroidism for up to 4 yr maintains the serum
calcium concentration, while significantly reducing supplemental calcium and 1,25-dihydroxyvitamin D requirements. Lumbar spine BMD increases without significant changes at other sites.
These data provide support for the safety and efficacy of PTH(1– 84) therapy in hypoparathyroidism
for up to 4 yr. (J Clin Endocrinol Metab 98: 137–144, 2013)
ypoparathyroidism is a disorder characterized by hypocalcemia and deficient PTH. It is the only classic
endocrine deficiency disease for which the missing hormone, PTH, is not yet an approved therapy. Standard
treatment consists of oral calcium and vitamin D supplementation. However, with standard therapy, maintaining normal serum calcium levels often presents a
therapeutic challenge. Concerns also exist regarding hypercalciuria and ectopic soft tissue calcification that can
H
be associated with long-term use of calcium and vitamin
D (1– 4).
Prior investigations suggest that PTH treatment is an
effective therapeutic option in hypoparathyroidism (5– 8).
We previously reported that treatment with PTH(1– 84)
for 2 yr in hypoparathyroid subjects led to reduced supplemental calcium and 1,25-dihydroxyvitamin D requirements (8), and similar observations were also reported in
a 6-month trial of PTH(1– 84) in hypoparathyroid sub-
ISSN Print 0021-972X ISSN Online 1945-7197
Printed in U.S.A.
Copyright © 2013 by The Endocrine Society
doi: 10.1210/jc.2012-2984 Received August 3, 2012. Accepted October 30, 2012.
First Published Online November 15, 2012
Abbreviations: BMD, Bone mineral density; CV, coefficient of variation; P1NP, propeptide
of type I collagen; TRAP, tartrate-resistant acid phosphatase 5b.
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Cusano et al.
PTH(1– 84) Therapy of Hypoparathyroidism
jects (7). However, given the chronic nature of hypoparathyroidism, long-term data on the safety and efficacy of
PTH use in this population are essential. In contrast to
osteoporosis, the potential duration of PTH therapy in
hypoparathyroidism may be greater than 2 yr. In this report, we describe the effects of PTH(1– 84) treatment on
biochemical, densitometric, and dynamic indices in hypoparathyroid patients for 4 yr. These are the longest-term
data to this point on the use of PTH therapy in this disease.
Subjects and Methods
Study design and protocol
Human recombinant PTH(1– 84) (NPS Pharmaceuticals,
Bedminster, NJ) was used to treat hypoparathyroid subjects for
4 yr, administered at a starting dose of 100 ␮g sc every other day.
This dose was based upon our previous experience demonstrating that this regimen restores reduced bone turnover markers in
hypoparathyroidism to levels that are within the normal range
(8). A single study physician titrated calcium and vitamin D supplementation to reach a target dose of 1.5 g/d of calcium and 0.25
␮g/d of 1,25-dihydroxyvitamin D. Monitoring was accomplished by review of symptomatology and regular measurements
of serum and urine calcium further detailed below.
Subjects
The diagnosis of hypoparathyroidism in men and women was
established by the simultaneous presence of serum calcium and
PTH concentrations below the lower limits of normal on at least
two occasions separated by at least 30 d. Hypoparathyroidism was
present for at least 2 yr to establish a chronic hypoparathyroid state.
All subjects had to be on stable regimens of supplemental calcium and
vitamin D intake for at least 6 months before enrollment. Subjects were
excluded if they had been on a bisphosphonate within 5 yr before study
entry or for more than 6 months at any time or if they were women
within 5 yr of menopause. Subjects were also excluded if they used any
of the following medications: estrogens, progestins, raloxifene, calcitonin,systemiccorticosteroids,fluoride,lithium,statins,loopdiuretics,
or methotrexate. The following potentially confounding disorders
were also exclusionary criteria: Paget’s disease of bone, diabetes mellitus, chronic liver or renal disease, acromegaly, Cushing’s syndrome,
rheumatoid arthritis, or multiple myeloma.
Patients were recruited from the Metabolic Bone Diseases
Unit of Columbia University Medical Center and from the Hypoparathyroidism Association. The study was approved by the
Institutional Review Board of Columbia University Medical
Center. All subjects gave written informed consent.
Of the 82 patients who provided written informed consent,
27 subjects have reached the 4-year time-point and are included
in this analysis. It seemed rational to present the data at this time
given this substantial number of subjects followed for this long
period. The other subjects are not part of this analysis for the
following reasons: three withdrew consent before administration of study drug; 24 have not yet reached the 4-yr time-point;
and 28 withdrew during yr 1– 4 because of the logistics of travel/
personal (n ⫽ 9), noncompliance/lost to follow-up (n ⫽ 8), adverse events not attributed to study drug (gastrointestinal illness,
vestibular neuritis, depression, headache/syncope; n ⫽ 4), unre-
J Clin Endocrinol Metab, January 2013, 98(1):137–144
lated health issues (n ⫽ 4), apparent recovery from hypoparathyroidism (n ⫽ 2), and nephrolithiasis (n ⫽ 1). The majority of
subjects (n ⫽ 16) withdrew within the first year.
Biochemical evaluation
Blood was obtained at baseline three times before treatment
and at months 1, 2, 3, 4, 5, 6, 9, 12, 18, 24, 30, 36, 42, and 48.
The average of three pretreatment serum calcium values was
used as the baseline calcium value. Blood sampling was performed 48 h after the last PTH injection. Biochemistries were
measured by automated techniques. Twenty-four-hour urinary
calcium excretion was measured at baseline and at 3, 6, 9, 12, 18,
24, 30, 36, 42, and 48 months.
Serum markers of bone turnover
Bone turnover markers were measured at baseline and months
6, 12, 18, 24, 30, 36, 42, and 48. Bone-specific alkaline phosphatase
was measured by enzyme immunoassay (Quidel, San Diego, CA);
inter- and intraassay coefficients of variation (CVs) were 8 and 6%,
respectively. N-mid osteocalcin was measured by ELISA [Immunodiagnostic Systems (IDS), Scottsdale, AZ]; inter- and intraassay
CVs were 4 and 2%, respectively. Propeptide of type I collagen
(P1NP) was measured by RIA (IDS); inter- and intraassay CVs were
8.3 and 6.5%, respectively. Collagen type 1 cross-linked C-telopeptide was measured by ELISA (IDS); inter- and intraassay CVs
were 10.9 and 3%, respectively. Tartrate-resistant acid phosphatase 5b (TRAP) was measured by ELISA (IDS); inter- and intraassay
CVs were 9 and 5%, respectively.
Safety outcomes
In addition to the time-points listed above, serum calcium
concentration was measured 1 and 2 wk after initiation of
PTH(1– 84). Serum calcium was measured 1 wk after each reduction in calcium or 1,25-dihydroxvitamin D supplementation
to ensure stability of the serum calcium concentration. If symptoms of hypocalcemia, such as numbness or paresthesias, developed, upward adjustments in calcium or 1,25-dihydroxyvitamin
D dosing were made. Information regarding adverse events was
recorded at each study visit.
Bone mineral density (BMD)
Areal BMD was measured at the lumbar spine (L1–L4), total
hip, femoral neck, and distal one third radius by dual x-ray absorptiometry (Hologic, Waltham, MA). Subjects were measured on the
same densitometer, using the same software, scan speed, and technologist, certified by the International Society of Clinical Densitometry. Measurements were performed twice at baseline and at
months 6, 12, 18, 24, 30, 36, 42, and 48. The average value of two
pretreatment BMD measurements was used for the baseline value.
Short-term in vivo precision error (root-mean-square SD) was 0.026
g/cm2 for L1–L4 (1.1%), 0.041 g/cm2 for the femoral neck (2.4%),
and 0.033 g/cm2 (1.8%) for the forearm.
Statistical analysis
A linear mixed model for repeated measures approach was applied with a single fixed effect of time and baseline level of the
outcome entered as a continuous covariate. The autoregressive covariance structure (1) was determined before inferential testing to
provide the best covariance model fit across all of the outcomes to
be tested. This analysis assesses the reliability of the within-subject
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change from baseline (SAS Proc MIXED, version 9.2; SAS Institute,
Cary, NC). Calcium and 1,25-dihydroxyvitamin D supplementation requirements were compared between the group of subjects
that discontinued therapy before 4 yr and the 27 subjects included
in this analysis. Subjects with at least a 50% decrease in both calcium and 1,25-dihydroxyvitamin D supplementation were also analyzed separately, consistent with the endpoints in the recently completed pivotal clinical trial (NCT00732615; Ref. 9). For the
categorical determination of changes in urinary calcium, the 42month urinary calcium values were used in three patients with missing 48-month values. Z-Scores for bone turnover markers were
calculated with normal ranges for men and pre- and postmenopausal women. Data in the body of the text are reported as modelestimated means and SD values, and differences between baseline
and subsequent times were tested by simultaneous confidence intervals. P values ⬍0.05 were used to establish significance. No adjustment for multiple comparisons was made for testing different
dependent variables.
Results
Baseline characteristics
Table 1 shows baseline characteristics of the 27 subjects. The mean age was 51 yr (range, 25– 68), and 74%
139
were women, consistent with the demographics of the disease. The two major etiologies of hypoparathyroidism
were postsurgical and autoimmune disease. The duration
of hypoparathyroidism ranged from 2 to 46 yr. Baseline
biochemistries and BMD are also shown in Table 1. Serum
calcium concentration was typically normal as a result of
supplementation with calcium and vitamin D. BMD was
normal or above average for a young, normal population.
Calcium and vitamin D supplementation
Supplemental calcium requirements fell significantly by
6 months after treatment was initiated with PTH(1– 84)
and remained lower throughout the study period. The average reduction in calcium supplementation was 37%,
from 2.7 ⫾ 3 g/d at baseline to 1.7 ⫾ 3 g/d at 4 yr (P ⫽
0.006; Fig. 1). The number of subjects who required more
than 1.5 g/d of calcium supplementation fell from 19
(70%) at study entry to 12 (44%) at study conclusion.
1,25-Dihydroxyvitamin D requirements also fell significantly by 45% from 0.65 ⫾ 0.7 ␮g/d at baseline to 0.36 ⫾
0.7 ␮g/d at 4 yr (P ⫽ 0.008; Fig. 1). Seven subjects (26%)
were able to discontinue all 1,25-dihydroxyvitamin D
TABLE 1. Baseline characteristics of the hypoparathyroid population
Age (yr)
Sex
Etiology
Duration of hypoparathyroidism (yr)
Fractures in adulthood (no. of patients)
Kidney stones (no. of patients)
Basal ganglia calcifications (no. of patients)
Calcium supplement dose (g/d)
1,25-dihydroxyvitamin D supplement dose (␮g/d)
Daily vitamin dose (IU/d)
Thiazide dose (mg/d) 关n ⫽ 7兴
Serum calcium (mg/dl)b
PTH (pg/ml)
Creatinine (mg/dl)
Phosphate (mg/dl)
Total alkaline phosphatase activity (U/liter)
Urinary calcium excretion (mg/d)
25-hydroxyvitamin D (ng/ml)
1,25-dihydroxyvitamin D (pg/ml)
Lumbar spine BMD (g/cm2)
Lumbar spine T-score
Total hip BMD (g/cm2)
Total hip T-score
Femoral neck BMD (g/cm2)
Femoral neck T-score
One third radius BMD (g/cm2)
One third radius T-score
n ⴝ 27
51 ⫾ 12
Female, 20 (premenopausal, 10;
postmenopausal, 10)
Male, 7
Postoperative, 16
Autoimmune, 10
DiGeorge, 1
20 ⫾ 15
9a
3
3
2.73 ⫾ 2.9
0.65 ⫾ 0.7
9,590 ⫾ 28,000
32 ⫾ 10
8.43 ⫾ 2.2
5⫾4
1.01 ⫾ 0.3
4.4 ⫾ 2
67 ⫾ 40
269 ⫾ 340
65 ⫾ 70
34 ⫾ 20
1.21 ⫾ 0.1
⫹1.51 ⫾ 2.0
1.07 ⫾ 0.1
⫹0.84 ⫾ 1.3
0.94 ⫾ 0.1
⫹0.67 ⫾ 1.5
0.73 ⫾ 0.1
⫹0.15 ⫾ 1.0
Range (median)
25– 68 (52)
2– 46 (16)
0 –9.0 (2.0)
0 –3.0 (0.5)
0 –100,000 (400)
25–50 (25)
6.6 –10.1 (8.5)
⬍1–14.2 (3)
0.60 –1.50 (0.95)
2.6 –5.8 (4.4)
40 –116 (70)
53– 499 (249)
9 –323 (31)
14 –100 (26)
0.89 –1.91
⫺1.40 to ⫹ 7.90
0.65–1.46
⫺2.40 to ⫹ 4.20
0.64 –1.30
⫺1.85 to ⫹ 3.60
0.60 – 0.90
⫺1.60 to ⫹ 1.55
Values are expressed as mean ⫾ SD unless described otherwise.
a
Normal range
Among the nine subjects, there were 10 digit fractures, two wrist, three hand, three rib, and one skull fracture.
b
Serum calcium concentration was typically normal as a result of calcium and vitamin D supplementation.
c
For men, 50 –300 mg/d.
8.6 –10.2
10 – 64
0.50 –1.30
2.5– 4.5
33–96
50 –250c
30 –100
15– 60
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Cusano et al.
PTH(1– 84) Therapy of Hypoparathyroidism
J Clin Endocrinol Metab, January 2013, 98(1):137–144
centration increased by 0.6 mg/dl but remained well
within the normal range (8.4 ⫾ 2 to 9.0 ⫾ 2 mg/dl; P ⫽
0.006). The serum calcium then returned to the baseline
value and did not change thereafter (Fig. 2). Urinary calcium excretion was significantly decreased over the course
of 4 yr (P ⫽ 0.003) and fell significantly below baseline
during yr 1, 2 (month 30; data not shown), and 3. Although urinary calcium excretion at yr 4 was still below
pretreatment values, the difference did not achieve statistical significance. The group seemed to divide itself into
those whose urinary calcium excretion fell by at least 10%
(n ⫽ 15) over the 4 yr, those who demonstrated an increase
in urine calcium excretion (n ⫽ 6), and those without a
FIG. 1. Changes in calcium and 1,25-dihydroxyvitamin D
supplementation. Calcium requirements decreased by 6 months from
baseline whereas 1,25-dihydroxyvitamin D requirements decreased by
36 months. Data are expressed as mean ⫾ SE. *, P ⬍ 0.05 compared
with baseline; †, P ⬍ 0.01 compared with baseline.
supplementation. After changes to calcium and 1,25-dihydroxyvitamin D supplementation, some patients required PTH dose adjustments to 100 ␮g every 3 d (n ⫽ 2)
or 100 ␮g daily (n ⫽ 5). Due to the availability of a new
50-␮g dose during the 4-yr time period of the study, the
dose of PTH was adjusted for some patients to 50 ␮g daily
between yr 3 and 4 (total n ⫽ 9), the majority after month
42. There were no statistical differences at 12 months between the group that discontinued before 4 yr and the
cohort included in this analysis with regard to calcium
(P ⫽ 0.69) and 1,25-dihydroxyvitamin D (P ⫽ 0.35) supplementation requirements.
Twelve subjects (44%) were able to reduce their supplementation of both calcium and 1,25-dihydroxyvitamin
D by at least 50%. In these subjects, calcium supplementation fell by an average of 61%, from 3.3 ⫾ 3 g/d at
baseline to 1.3 ⫾ 3 g/d at 4 yr (P ⫽ 0.002). 1,25-Dihydroxyvitamin D requirements fell by 64%, from 0.73 ⫾
0.5 ␮g/d at baseline to 0.26 ⫾ 0.5 ␮g/d at 4 yr (P ⫽ 0.001).
Serum and urinary calcium levels, other indices of
mineral metabolism
During the first 6 months of PTH(1– 84) treatment,
while oral calcium and 1,25-dihydroxyvitamin D supplementation was titrated downward, the serum calcium con-
FIG. 2. Changes in serum calcium, urinary calcium, and serum
phosphorus. Serum calcium was no different from baseline after 6
months through study conclusion. During the first 6 months of the
study, there were small but significant increases from baseline within
the normal range. Urinary calcium decreased significantly at months 12
and 36 and tended to be lower at 48 months. Serum phosphorus
decreased and remained in the normal range throughout the study
period. Data are expressed as mean ⫾ SE. *, P ⬍ 0.05 compared with
baseline.
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141
FIG. 3. Changes in BMD. Lumbar spine BMD increased, whereas the total hip and femoral neck did not change and the distal one third radius
BMD decreased. Data are expressed as mean ⫾ SE. *, P ⬍ 0.05 compared with baseline; ‡, P ⬍ 0.0001 compared with baseline.
significant change in urinary calcium excretion (n ⫽ 3;
data missing for n ⫽ 3). Among those whose calcium and
1,25-dihydroxyvitamin D requirements both fell by at
least 50%, urinary calcium excretion also fell by 50%,
from 324 ⫾ 360 mg/d at baseline to 162 ⫾ 390 mg/d at 4
yr (P ⫽ 0.03). In the entire cohort, the trend for serum
phosphorus was a significant decline over the course of the
study (P ⫽ 0.006).
Bone mineral density
Lumbar spine BMD increased by 2.0 ⫾ 7% at 18
months (P ⫽ 0.01) and continued to increase throughout
the study period, reaching a mean gain of 5.5 ⫾ 9% at 4
yr (P ⬍ 0.0001) (Fig. 3). Femoral neck (⫹0.6 ⫾ 12% at 4
yr; P ⫽ 0.71) and total hip (⫹1.1 ⫾ 9% at 4 yr; P ⫽ 0.37)
BMD remained essentially unchanged. BMD at the distal
one third radius, which had shown a modest but significant decline at 2 yr (⫺2.0 ⫾ 6%; P ⫽ 0.018), did not
progress further and was not significantly different from
baseline at the end of the 4-yr period (⫺1.8 ⫾ 8% from
baseline; P ⫽ 0.063). The BMD response was not dependent on the extent to which calcium and 1,25-dihydroxyvitamin D requirements fell.
Bone turnover markers
All bone turnover markers were in the low- to midnormal range at baseline (Z-score range, ⫺1.7 to ⫹0.3).
With PTH(1– 84) treatment, all bone turnover markers
increased significantly, peaking up to 3-fold above baseline values by 6 –12 months (Fig. 4). Thereafter, bone turnover markers declined to steady-state levels by 30 months.
This steady state was higher than pretreatment values (Zscore, ⫺0.7 to ⫹2.0), although statistically significant
only for TRAP and P1NP (P ⫽ 0.016 and P ⫽ 0.046 from
baseline to 4 yr, respectively). For the next 18 months,
bone turnover markers were consistently measured at
these values.
Adverse events
There were 11 episodes of mild hypercalcemia in eight
subjects over 4 yr (1.9% of all values), most occurring
within the first 6 months and resolving with adjustment of
supplemental calcium and vitamin D. No hypercalcemic
events required hospitalization. The most common adverse events were musculoskeletal, gastrointestinal, and
genitourinary complaints (Table 2). Other adverse events
over 4 yr included two fractures (yr 1, elbow; yr 4, toe) and
one episode of nephrolithiasis (yr 4). The subject that developed nephrolithiasis had 14 normal serum calcium values documented from month 2 through month 48 of the
study and demonstrated a greater than 10% reduction in
urine calcium excretion.
Discussion
This is the first study to report the extended use of any PTH
therapy in a well-described cohort over 4 yr, in hypoparathyroidism or any other metabolic bone disease. PTH(1–
84) therapy returned the abnormally low bone turnover
state characteristic of hypoparathyroidism, as measured
by bone turnover markers, to more normal levels after a
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PTH(1– 84) Therapy of Hypoparathyroidism
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TABLE 2. Adverse events in subjects treated with
PTH(1– 84) over 4 yr
Symptoms/complaints
Adverse events
Musculoskeletal
Gastrointestinal
Genitourinary
Mental and mood
Fatigue
Infections
Headache
Dermatologic
Nausea
Hypercalcemia
Dizziness
Paresthesias
Insomnia
Thirst
Othera
Serious adverse eventsb
Year 1
Year 2
Year 3
Year 4
59 (78)
21 (48)
16 (48)
21 (44)
15 (44)
17 (37)
12 (37)
11 (33)
11 (30)
9 (26)
7 (26)
14 (22)
8 (22)
5 (19)
37 (52)
2 (4)
22 (44)
3 (7)
3 (11)
5 (11)
1 (4)
5 (19)
4 (15)
1 (4)
2 (4)
2 (7)
2 (7)
2 (7)
1 (4)
0
16 (44)
4 (11)
15 (37)
3 (11)
3 (11)
3 (7)
1 (4)
4 (11)
0
3 (11)
3 (11)
0
1 (4)
1 (4)
0
0
7 (26)
2 (4)
20 (52)
1 (4)
4 (11)
2 (4)
5 (15)
5 (19)
1 (4)
3 (11)
0
0
0
2 (7)
3 (11)
0
12 (26)
2 (7)
Data are expressed as number of events (percentage of subjects).
a
Includes two fractures (yr 1, elbow; yr 4, toe) and one episode of
nephrolithiasis (yr 4).
b
Year 1, Hospital admissions for right flank pain, concussion after
motor vehicle accident (same patient); yr 2, hospital admissions
for hypocalcemia (three patients); yr 3, hospital admissions for
hypocalcemia (same patient); yr 4, hospital admissions for
hypocalcemia, dehydration.
FIG. 4. Changes in markers of bone formation (P1NP, BALP, OCN; A)
and resorption (CTX, TRAP; B) over 4 yr of PTH(1– 84). With PTH(1– 84)
treatment, all bone turnover markers increased significantly, peaking
up to 3-fold from baseline values at 6 –12 months and subsequently
declining to steady-state levels at 30 months. BALP, Bone-specific
alkaline phosphatase; OCN, N-mid osteocalcin; CTX, collagen type 1
cross-linked C-telopeptide. Data are expressed as mean ⫾ SE. *, P ⬍
0.05 compared with baseline; †, P ⬍ 0.01 compared with baseline;
‡, P ⬍ 0.0001 compared with baseline.
period of heightened responsiveness. The results also confirm that PTH(1– 84) therapy in hypoparathyroidism significantly reduces calcium and 1,25-dihydroxyvitamin D
requirements, maintains stable serum calcium concentrations, and tends to reduce urinary calcium excretion. This
long-term experience also documents that treatment with
PTH(1– 84) was well tolerated. In particular, hypercalcemia was very uncommon.
It is of interest to compare our results to those of Winer
et al. (5) and Sikjaer et al. (7), using PTH(1–34) and
PTH(1– 84), respectively, in adults with hypoparathyroidism. Winer et al. (5) randomized hypoparathyroid subjects
to receive either open-label PTH(1–34) in divided doses
averaging 37 ␮g or 1,25-dihydroxyvitamin D for 3 yr.
Sikjaer et al. (7) studied hypoparathyroid subjects randomized to PTH(1– 84) 100 ␮g daily vs. placebo for 6
months. Both forms of PTH were shown to have salutary
effects on the management of hypoparathyroidism with
respect to calcium and 1,25-dihydroxyvitamin D supple-
mentation requirements. PTH(1–34) normalized urine
calcium excretion (5), and our study as well demonstrated
a trend toward a decline in urine calcium excretion with
PTH(1– 84). An increase in renal tubular absorption of
calcium indicates that PTH therapy may help to restore
normal renal PTH physiology. It is also evident that comorbidities in hypoparathyroid patients are due, at least in
part, to the high calcium and vitamin D supplement requirements with subsequent risk for ectopic soft tissue
calcification. It is reasonable to expect, therefore, that the
reduction in calcium and vitamin D supplement requirements when PTH is used in hypoparathyroidism may well
be associated over time with a reduction in complications.
The bioavailability of PTH(1– 84) is longer than PTH(1–
34) (10, 11), which may help to explain why dosing with
PTH(1–34) has required multiple injections per day
whereas with PTH(1– 84), single daily dosing and every
other day dosing appears to provide good results.
We found that BMD at the lumbar spine was above
average at baseline and continued to increase throughout
the study period, whereas BMD at the hip was unchanged.
BMD at the distal one third radius, which showed early
declines at 2 yr (8), did not progress further. These densitometric results are compatible with the differential effects of PTH at sites that are predominantly cortical (distal
one third radius) or trabecular (lumbar spine) (12–16).
Although bone density continued to increase at the lumbar
J Clin Endocrinol Metab, January 2013, 98(1):137–144
spine, the microstructural basis for this change is not yet
clear. Based upon the bone turnover marker data and what
is known about the osteoanabolic effect of PTH, the increase in BMD at the lumbar spine might reflect not simply
more bone mineral but also improvement in the microstructural features of the accrued bone. The lack of change
in BMD at the distal one third radius does not imply that
cortical bone is not enhanced by PTH(1– 84) because expected salutary effects on microarchitecture and bone size
could provide biomechanical advantages despite stable
BMD. These expectations are supported by a histomorphometric analysis of bone biopsies from 64 subjects with
hypoparathyroidism who were treated with PTH(1– 84).
After 2 yr, structural and dynamic properties of bone were
improved by PTH(1– 84) (17). Although the results of the
current study suggest that these improved microstructural
features of bone are maintained over a longer period of
time, further direct analyses of bone by bone biopsy after
4 yr of PTH(1– 84) will be needed to substantiate this
likelihood.
In contrast to our results, Sikjaer et al. (7) showed a very
small but significant reduction in lumbar spine BMD
(⫺1.76 ⫾ 1.0%) with PTH(1– 84), but these results are
not easily comparable because of the very short 6-month
duration of the trial by Sikjaer et al. (7). Winer et al. (5)
found no increase in lumbar spine BMD after 3 yr. In their
study, bone turnover markers rose slowly, reaching a peak
only after 2.5 yr, after which they declined over the next
6 months. These kinetics are different from our observations with PTH(1– 84) in which bone turnover markers
peaked much earlier and then declined to steady-state levels by 30 months, with P1NP and TRAP remaining statistically higher than baseline at 4 yr. Bone biopsies at
baseline, 3, 12, and 24 months from our earlier work (17)
substantiate these circulating bone turnover kinetics with
increases and then decreases in histomorphometrically determined skeletal dynamics over a similar time course.
These observations may indicate that the relatively shortacting PTH(1–34) at a dose approximately three times our
equivalent dose of PTH(1– 84) (18) is not as beneficial to
bone dynamics as PTH(1– 84), the natural hormone.
The strengths of this investigation include the unusually
large cohort of subjects with hypoparathyroidism that
was studied, the use of PTH(1– 84), the natural secretory
product of the parathyroid glands, and its longitudinal
design. The limitations of the study include the open-label
protocol and the lack of a control group not treated with
PTH(1– 84). However, each patient served as his/her own
control with which specific changes could be carefully
monitored. The stability of calcium and 1,25-dihydroxyvitamin D requirements before therapy with
PTH(1– 84) supports the conclusion that PTH-associated
jcem.endojournals.org
143
reductions in those supplements are unlikely to have occurred spontaneously. Moreover, a randomized, placebocontrolled study of PTH(1– 84) is being reported in which
these data are most consistent. In that study (9), the percentage of subjects who were able to reduce their requirements by more than 50% (53.5%), as well as the percentage of subjects who could entirely eliminate their need for
1,25-dihydroxyvitamin D (41.1%) are all similar to the
results of this study.
Every other day injectable PTH(1– 84) does not simulate normal PTH tonic and pulsatility dynamics. In the
future, perhaps, it might be possible to mimic more closely
the dynamics of constant PTH secretion (6). The dose regimen for a number of subjects was adjusted during the
duration of the study, which indicates that this therapy
will likely have to be titrated on an individual basis to
achieve the best results. Because the study design called for
serum and urine measurements after the first 24 h of PTH
administration, earlier changes in serum and urinary analytes, if they occurred, would have been missed. In a study
investigating the pharmacodynamics of PTH(1– 84) 100
␮g daily in hypoparathyroid patients (19), 41% of subjects developed mild asymptomatic hypercalcemia. However, the dose of PTH was higher than that used in our
study, and the baseline serum calcium was substantially
higher than in our subjects. Based upon the small increments in serum calcium after administration of PTH(1–
84) in healthy postmenopausal women (20) and serum
and urine calcium excursion in subjects with hypoparathyroidism (19), we do not believe that our subjects would
have experienced significant hypercalcemia or hypercalciuria in the time period preceding our measurement.
These limitations do not alter the main conclusions of
the study that demonstrate clearly that PTH(1– 84) is safe
and effective as a long-term treatment of hypoparathyroidism for up to 4 yr. Longer-term studies will help elucidate whether the major comorbidities associated with
hypoparathyroidism are reduced or reversed with PTH
therapy.
Acknowledgments
The authors acknowledge Elzbieta Dworakowski, Laura Anderson, Wendy Fan, and Zachary Lenane.
Address all correspondence and requests for reprints to:
John P. Bilezikian, M.D., Columbia University College of Physicians & Surgeons, Division of Medicine, 630 West 168th
Street, PH 8W-864, New York, New York 10032. E-mail:
[email protected].
This work was supported by National Institutes of Health
Grants DK069350 and DK095944, Food and Drug Administration Grant 002525, and NPS Pharmaceuticals.
144
Cusano et al.
PTH(1– 84) Therapy of Hypoparathyroidism
Disclosure Summary: J.P.B. is a consultant for Amgen, Eli
Lilly, Radius, NPS Pharmaceuticals, Merck, Warner Chilcott,
and GSK and receives research support from NPS Pharmaceuticals and Amgen. M.R.R. receives research support from NPS
Pharmaceuticals. S.C.C. is a consultant for Roche Diagnostics,
Immunodiagnostics, Brains-Online, and Thar Pharmaceuticals
and receives research support from Roche Diagnostics. No conflicts of interest are reported for the remaining authors.
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