The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 8 2739-2743
Copyright © 1999 by The Endocrine Society
Comparison of the Biochemical Responses to Human Parathyroid Hormone-(1–31)NH2 and hPTH-(1–34) in Healthy Humans1
L. J. Fraher,
R. Avram,
P. H. Watson,
G. N. Hendy,
J. E. Henderson,
K. L. Chong,
D. Goltzman,
P. Morley,
G. E. Willick,
J. F. Whitfield and
A. B. Hodsman
Departments of Medicine (L.J.F., R.A., P.H.W., A.B.H.) and
Biochemistry (L.J.F.), The Lawson Research Institute, St. Joseph’s
Health Center, University of Western Ontario, London, Ontario, Canada
N6A 4V2; the Departments of Medicine and Physiology (G.N.H., J.E.H.,
K.L.C., D.G.), McGill University, Montreal, Quebec, Canada; and
the Institute for Biological Sciences, National Research Council (P.M.,
G.E.W., J.F.W.), Ottawa, Ontario, Canada
Address all correspondence and requests for reprints to: Dr. Laurence J. Fraher, Room G-442, St. Joseph’s Health Center, 268 Grosvenor Street, London, Ontario, Canada N6A 4V2. E-mail:
lfraher{at}lri.stjosephs.london.on.ca
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Abstract
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The 1–31 fragment of human PTH [hPTH-(1–31)NH2] has
been shown, like hPTH-(1–34), to have anabolic effects on the
skeletons of ovariectomized rats when given intermittently, but, unlike
hPTH-(1–34), it does so without affecting serum calcium concentrations
and does not activate the protein kinase C second messenger pathway in
some target cells. To investigate the biochemical responses to
hPTH-(1–31) in humans, we have directly compared it to hPTH-(1–34)
during the course of slow infusions of each. Ten healthy adults, five
men and five women, aged 26 ± 5 yr (range, 22–37), each received
8-h continuous infusions of 8 pmol/kg·h hPTH-(1–34) and hPTH-(1–31)
given in random order at least 2 weeks apart. During the infusions
there were significant increases in both plasma and urinary cAMP
(P < 0.05), but there were no differences in the
responses between the two peptides (P = 0.362 for
plasma; P = 0.987 for urine). There were also
significant phosphaturic and natriuretic responses to the two peptides,
which again were not different between peptides. During the infusion of
hPTH-(1–34) serum ionized calcium (Ca2+) increased from
1.21 ± 0.033 to 1.29 ± 0.046 mmol/L (P
< 0.01), and endogenous hPTH-(1–84) decreased from 29.6 ± 9 to
15.0 ± 5.7 pg/mL (P < 0.01), such that there
was a negative correlation between them (r2 = 0.45).
However, when hPTH-(1–31) was infused, neither serum Ca2+
(1.24 ± 0.03 vs. 1.25 ± 0.03) nor
hPTH-(1–84) (26.8 ± 5 vs. 30.7 ± 12 pg/mL)
was affected. Circulating concentrations of 1,25-dihydroxyvitamin
D3 increased from 92 ± 42 to 131 ± 63 pmol/L
(P < 0.05) during infusion of hPTH-(1–34) and
from 92 ± 27 to 110 ± 42 pmol/L (P =
NS) during hPTH-(1–31) infusion. There was also a significant increase
in the urinary measure of type I collagen degradation of amino-terminal
telopeptides from 78 ± 45 to 101 ± 51 nmol/mmol creatinine
(P < 0.05) when hPTH-(1–34) was infused, but it
was not affected (68 ± 30 vs. 66 ± 24
nmol/mmol creatinine) by hPTH-(1–31). Therefore, hPTH-(1–31) appears
to be equivalent and equipotent to hPTH-(1–34) in the release of cAMP
from target tissues and the renal handling of phosphate and sodium.
However, at the doses employed, it does not increase serum calcium, is
a weaker stimulator of the 25-hydroxyvitamin D-1
-hydroxylase, and
does not induce rapid bone resorption.
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Introduction
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AMINO-TERMINAL fragments of PTH are
potent anabolic agents for the treatment of osteoporosis because they
can strongly stimulate the production of cortical and trabecular bone
in ovariectomized rats (1, 2, 3, 4) and humans (5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15). Over the 25 yr of
experience of using PTH in treating patients with osteoporosis, the
majority of studies have employed the use of synthetic human (h)
PTH-(1–34), although some have used the longer hPTH-(1–38) fragment
(6, 7, 8). Although all of these studies have demonstrated the beneficial
effects of PTH therapy, it is recognized that the limiting factor to
its widespread clinical usage is hypercalcemia and mild renal
impairment, as noted by Hodsman et al. (16, 17). A new PTH
fragment, hPTH-(1–31), has been extensively evaluated in the
ovariectomized rat model of osteoporosis and has proven to be as potent
as hPTH-(1–34) while having no apparent hypercalcemic effect in these
animals (18, 19, 20, 21). In vitro studies using transformed
osteoblast cell lines from rats have suggested that although
hPTH-(1–34) is capable of stimulating both protein kinase A and
protein kinase C pathways, hPTH-(1–31) only activates protein kinase A
(22, 23, 24). However, in a more recent study, in which the human PTH/PTHrP
receptor was stably transfected into a porcine kidney cell line,
hPTH-(1–31) appeared to be equipotent with hPTH-(1–34) in activating
both the adenylate cyclase and phospholipase C systems (25). Although
we did not attempt to resolve the issue of the precise intracellular
pathways by which hPTH-(1–31) activates its target tissues, we were
interested to evaluate its effects on a variety of biochemical
parameters and compare it to hPTH-(1–34) in vivo in healthy
humans. Therefore, in the current study we have examined the biological
effects of hPTH-(1–31) when infused at physiological doses over an 8-h
period and compared then to those of an equimolar dose of hPTH-(1–34),
which has previously been extensively characterized (26, 27).
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Subjects and Methods
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Subjects
The study protocol was approved by the review board for research
involving human subjects at the University of Western Ontario. Ten
healthy volunteers were recruited, five men and five women, aged 22–37
yr (mean age, 26 ± 5 yr). After informed consent was obtained,
each subject received two test infusions, given in random order spaced
at least 2 weeks apart, of hPTH-(1–34) at a dose of 8 pmol/kg·h
(equivalent to 0.5 IU/kg·h) or hPTH-(1–31) at a dose of 8
pmol/kg·h. Each infusion was given over 8 h between 1000–1800 h
via a peripheral vein, using a Pharmacia IVAC infusion pump
(Pharmacia Biotech, Piscataway, NJ). Venous samples were
obtained from the contralateral arm into heparinized tubes 15 min
before and 0, 1, 2, 4, 6, 8, and 24 h after the start of the
infusion. Plasma was separated and frozen at -70 C within 30 min. At
0, 4, and 8 h, blood samples were taken into serum separation
tubes, kept on ice, separated, and analyzed for ionized calcium within
1 h. On each test day, six urine collections were made at -2 to
0, 0–1, 1–2, 2–4, 4–6, and 6–8 h and aliquoted before storage at
-20 C for analysis as described below.
Methods
Synthetic hPTH-(1–34) was a gift from Rhone Poulenc Rorer
Pharmaceutical (Horsham, PA), and synthetic hPTH-(1–31) was
synthesized by Sheldon Biotechnology Center, McGill University
(Montreal, Canada). The preparation of hPTH-(1–31) was synthesized
according to good manufacturing practices and purified to a single peak
by high pressure liquid chromatography, and its sequence was confirmed
by amino acid analysis. The in vitro potency of each peptide
was confirmed and compared by parallel assays of each in two biological
assays: 1) an adenylate cyclase assay system in both UMR 106
osteoblasts and OK/E kidney cells (28), and 2) a determination of
inhibition of sodium-dependent phosphate transport in OK/E cells (29).
The activities of the two peptides were identical in the two assay
systems.
Serum calcium (Ca), inorganic phosphate (PO4), creatinine,
and alkaline phosphatase together with urinary PO4,
potassium (K), sodium (Na), chloride (Cl), and creatinine were measured
by standard automated techniques. Urinary calcium was measured by
atomic absorption spectroscopy, and serum ionized calcium
(Ca2+) was determined by ion-selective electrode (Ciba
Corning Diagnostic, Medfield, MA) with a reference range of 1.15–1.30
mmol/L. Serum intact immunoassayable PTH-(1–84) was measured by a
two-site immunoradiometric assay (DiaSorin, Inc.)
with a reference range of 5–35 pg/mL. Plasma and urinary cAMP were
measured by RIA (DiaSorin, Inc.). Plasma
1,25-dihydroxyvitamin D3
[1,25-(OH)2D3] was measured as previously
described with a reference range of 48–156 pmol/L in young adults
(30), and urinary amino-terminal telopeptides of type I collagen (NTx)
were measured using an enzyme-linked immunosorbent assay (Osteomark,
Ostex International, Inc. Seattle, WA) with a normal range
of up to 200 nmol/mmol creatinine.
Statistical analysis
In the text the data are expressed as the mean ±
SD, and for the figures, error bars are SEMs.
Comparisons were made between each treatment at specified time points
by a repeated measures ANOVA. Within-treatment peak changes in the
measured variables compared to baseline were assessed by paired
Student’s t test.
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Results
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All 10 subjects completed the full study protocol with no
side-effects noted. During the infusions, plasma cAMP increased from
16.1 ± 9.6 to a peak at 2 h of 35.6 ± 24 pmol/L with
hPTH-(1–34) and from 19.4 ± 5.8 to 29.7 ± 8.7 pmol/L at
2 h when hPTH-(1–31) was infused (Fig. 1
, upper panel). Although
within each infusion these changes were significant (P
< 0.05), there were no differences between the magnitude of change
between the infusions (interaction, P = 0.362).
Similarly, as shown in the lower panel of Fig. 1, when
hPTH-(1–34) was infused, urinary cAMP increased from 3.37 ± 1.1
pmol/mmol creatinine (-2 to 0 h) to a peak of 6.92 ± 4.48
pmol/mmol creatinine during the second hour of the infusion (1–2 h;
P < 0.05); with hPTH-(1–31), the increase was from
3.84 ± 2.95 to 7.36 ± 5.1 pmol/mmol creatinine
(P < 0.05). Again, there were no differences between
the effects of either peptide (interaction, P = 0.987).
Table 1 shows the urinary biochemistry
for selected variables expressed per mmol creatinine, and in Fig. 2 the changes in the fractional excretion
of phosphate before and at the end of the 8-h infusions. There were no
significant differences in the degree of the phosphaturic or
natriuretic response between the two infusions, although both the
absolute (Table 1) and the fractional excretion (Fig. 2) of phosphate
were slightly greater during the infusion of hPTH-(1–34). Urinary
calcium excretion increased steadily during the latter half (4- to 6-h
and 6- to 8-h collections) of both infusions, increasing by some 55%
at 8 h during the infusion of hPTH-(1–34) and by some 74% with
hPTH-(1–31); however, neither reached statistical significance (Table 1).
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Figure 1. Concentrations of cAMP in plasma
(upper panel) and urine, corrected for creatinine
content (lower panel), before and at the peak response
during infusions of either hPTH-(1–34) (solid circles)
or hPTH-(1–31) (open circles) in 10 healthy adults.
Values are the mean ± SEM. *, P
< 0.05.
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Figure 2. Changes in the fractional excretion of
phosphate during the infusion of either hPTH-(1–34) (closed
circles) or hPTH-(1–31) (open circles) in 10
healthy adults. **, P < 0.01.
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During the 8-h infusion of hPTH-(1–34), total serum calcium increased
by 0.12 ± 0.07 mmol/L from 2.38 ± 0.5 to 2.50 ± 0.1
mmol/L (P < 0.01), but by only 0.03 ± 0.05
mmol/L from 2.43 ± 0.07 to 2.46 ± 0.08 mmol/L after the
infusion of an equimolar dose of hPTH-(1–31). ANOVA showed that there
was a significant (P < 0.01) difference between these
responses. Shown in Fig. 3 are sequential
observations of the concentrations of serum ionized calcium and
endogenous plasma immunoreactive hPTH-(1–84) during the course of the
two infusions and at 1000 h on each of the following days. During
the infusion of hPTH-(1–34) (Fig. 3, upper panel) ionized
calcium increased steadily from 1.21 ± 0.033 to 1.29 ±
0.046 mmol/L at 8 h (P < 0.01) and had fallen
again to 1.23 ± 0.04 mmol/L by 24 h. At the same time
endogenous hPTH-(1–84) fell from 29.6 ± 9.0 to 15.0 ± 5.7
pg/mL by 8 h (P < 0.01), and then returned to
28.1 ± 13.5 pg/mL by 24 h. In contrast, during the infusion
of hPTH-(1–31) (Fig. 3, lower panel), there were no
significant alterations in either ionized calcium or hPTH-(1–84)
during the course of the 24 h. ANOVA suggested that there were
significant differences in the responses of serum Ca2+ and
immunoassayable PTH-(1–84) between the two peptides (P
< 0.01). These differences are further illustrated in Fig. 4, in which the measured concentrations
of ionized calcium are related to those of hPTH-(1–84) in the
individual samples from the 10 subjects over the 2 test infusions.
During the infusion of hPTH-(1–34) there was a significant negative
linear regression between the 2 parameters, whereas no such
relationship was found when hPTH-(1–31) was infused.
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Figure 3. Changes in the concentrations of serum
ionized calcium (open circles) and immunoreactive
PTH-(1–84) (closed circles) during (hatched
bar) and after infusions of either hPTH-(1–34) (upper
panel) or hPTH-(1–31) (lower panel) in 10
healthy adults. Values are the mean ± SEM. *,
P < 0.05; **, P < 0.01.
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Figure 4. Relationship between the measured
concentrations of ionized calcium and immunoreactive PTH-(1–84) in
samples obtained at 0, 4, 8, and 24 h. Left, During
infusion of hPTH-(1–34) (P < 0.001);
right, lack of any significant relationship during
infusion of hPTH-(1–31).
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Changes in the concentrations of serum
1,25-(OH)2D3 and urinary NTx from the beginning
to the end of the infusions are shown in Fig. 5. 1,25-(OH)2D3
increased from 94 ± 42 to 131 ± 63 pmol/L with hPTH-(1–34)
(P < 0.05), but from only 92 ± 27 to 110 ±
42 pmol/L with hPTH-(1–31) (P = NS). Similarly,
urinary NTx increased from 78 ± 45 to 101 ± 51 nmol/mmol
creatinine with hPTH-(1–34) (P < 0.05) and did not
change during the infusion of hPTH-(1–31) (67.5 ± 30
vs. 65.6 ± 24 nmol/mmol creatinine).
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Figure 5. Concentrations of
1,25-(OH)2D3 in plasma (upper
panel) and NTx, corrected for creatinine content (lower
panel), before and at the end of infusions of either
hPTH-(1–34) (closed circles) or hPTH-(1–31)
(open circles) in 10 healthy adults. Values given are
the mean ± SEM. *, P < 0.05.
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Discussion
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This study shows that although hPTH-(1–31) and hPTH-(1–34) are
qualitatively and quantitatively similar in their abilities to generate
cAMP and inhibit the renal reabsorption of inorganic phosphorus and
sodium when given to healthy humans, hPTH-(1–31), compared to
hPTH(1–34), is 1) a weaker stimulator of the 25-hydroxyvitamin
D-1-hydroxylase, 2) does not result in the rapid resorption of bone,
and 3) does not appear to induce a calcemic response.
Increases in serum calcium are an important issue in view of the
potential widespread use of PTH to treat osteoporosis. Infusion of
either the holohormone or synthetic hPTH-(1–34) over prolonged periods
consistently increases the concentration of serum calcium. In response
to total infused doses of between 400–800 U hPTH-(1–34) given over
24 h, serum calcium rises by some 0.3–0.4 mmol/L (11, 13, 31). In
contrast, single sc injections of the same amounts of hPTH-(1–34)
produce a slow rise in serum calcium of about 0.1 mmol/L, which peaks
some 4–8 h postinjection (13, 32). With prolonged daily injections the
fasting serum calcium concentration at 24 h after the injection is
generally unchanged or only minimally greater than the baseline value,
with the total serum calcium remaining within the normal range (17).
However, this mode of peptide administration may not be free of
sequelae, as Hodsman et al. (16) have noted that patients
treated with 800 U hPTH-(1–34) daily for 28 days, repeating every 3
months, experience a significant 10% increase in serum creatinine over
2 yr. These rises in serum calcium are also associated with some degree
of suppression of the release of endogenous PTH. Both Finkelstein
et al. (8) and Hodsman et al. (16) reported an
approximately 50% reduction in the plasma concentration of
immunoreactive endogenous PTH 24 h after exogenous PTH
injection.
In the present study it was determined that infusion of 8 pmol/kg·h
hPTH-(1–34) over 8 h resulted in significant increases in both
ionized and total serum calcium, with the former increasing by some
0.08 mmol/L, and the latter by 0.12 mmol/L. Associated with these
increases, immunoreactive PTH-(1–84) in plasma decreased by half, from
30 to 15 pg/mL, such that there appeared to be a strong negative
correlation between ionized calcium and endogenous PTH under these
conditions. In contrast, when hPTH-(1–31) was infused, there were no
alterations in either serum calcium or immunoreactive PTH-(1–84).
However, the increases in both plasma and urinary cAMP produced during
the infusion of hPTH-(1–31) were of equal magnitude to those occurring
during the infusion of hPTH-(1–34). The effects of the two peptides on
the renal handling of phosphate, calcium, sodium, and potassium were
very similar; both induced a significant phosphaturic and natriuretic
response. The finding that infusion of hPTH-(1–31) resulted in an
increase in the urinary output of calcium, but had no effect on serum
calcium, is taken be due to a direct effect of the peptide on the
kidney, in that the calciuresis is linked to the loss of sodium, rather
than to a response to a rise in serum calcium per se.
Consistent with these effects in humans it should be noted that in
animal studies, hPTH-(1–31) has proven to be as effective as
hPTH-(1–34) in restoring both trabecular and cortical components of
the skeletons of ovariectomized rats (18, 19, 20, 21).
How is hPTH-(1–31) less effective in raising the serum calcium
concentration? Two mechanisms are suggested by the present study.
First, hPTH-(1–31) is apparently a weaker stimulator of the
25-hydroxyvitamin D-1-hydroxylase system, as the increases in
circulating 1,25-(OH)2D3 were not as great
during the infusion of hPTH-(1–31) as they were during hPTH-(1–34)
infusion. Second, hPTH-(1–31), in contrast to hPTH-(1–34), does not
stimulate bone resorption, as judged by the unaltered urinary type I
collagen N-terminal telopeptide NTx. This analyte reflects type I
collagen catabolism and, therefore, by inference is a marker of bone
resorption. During the infusion of hPTH-(1–34) the renal output of NTx
increased by some 30%, whereas it was unchanged when hPTH-(1–31) was
infused. Thus, unlike hPTH-(1–34), the hPTH-(1–31) fragment does not
result in significant stimulation of bone resorption when infused
continuously and, consequently, does not result in increased release of
calcium from the skeleton. Further studies are needed to explore this
issue; however, the present studies emphasize that assessment of the
clinical potential of hPTH-(1–31) as a bone anabolic agent in the
treatment of osteoporosis is warranted.
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Acknowledgments
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The authors thank the Departments of Pharmacy and Clinical
Biochemistry for assistance with the studies, and Dr. Larry Stitt,
Department of Epidemiology and Biostatistics, University of Western
Ontario, for performing the statistical analysis.
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Footnotes
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1 This work was supported by the Medical Research Council of Canada
(Grant MT-5775). 
Received February 24, 1999.
Revised April 5, 1999.
Accepted April 28, 1999.
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Abstract
Introduction
