Joint Bone Spine 70 (2003) 465–470

www.elsevier.com/locate/bonsoi

Clinical lectures

Efficacy data on teriparatide (parathyroid hormone)

in patients with postmenopausal osteoporosis
Françoise Debiais *
Rheumatology Department, Jean Bernard Hospital, 86021 Poitiers cedex, France
Received and accepted 19 August 2003

Abstract

Until recently, the only therapeutic agents available for postmenopausal osteoporosis acted by inhibiting bone resorption and decreased the
fracture risk by no more than 50%. Teriparatide, the recombinant 1–34 fragment of human parathyroid hormone, is a bone formation enhancer
that has recently been licensed for use in established postmenopausal osteoporosis. Intermittent parathyroid hormone administration
preferentially stimulates bone formation. The resultant increase in bone mass and improvement in bone architecture translate into a large
decrease in the fracture risk that constitutes a major advance in the treatment of postmenopausal osteoporosis. Further work is needed to define
the role for teriparatide in the therapeutic strategy for postmenopausal osteoporosis and to determine whether this agent is best used alone or
in synchronous or sequential combination with bone resorption inhibitors.
© 2003 Published by Éditions scientifiques et médicales Elsevier SAS.

Keywords: Parathyroid hormone; Anabolic agents; Postmenopausal osteoporosis

1. Introduction being 18 months. Whereas continuous exposure to PTH

The last few years have seen considerable progress in the
management of osteoporosis. However, until recently, the
only available drugs acted by inhibiting bone resorption. The
gains in bone mineral density (BMD) obtained with these
drugs are moderate and mainly ascribable to an increase in
mean bone tissue mineralization [1]. The fracture risk de-
crease does not exceed 50%. The recent development of
anabolic agents that afford far greater protection against new
fractures is a major breakthrough in the treatment of post-
menopausal osteoporosis. To date, teriparatide is the only
anabolic agent licensed for use in osteoporosis. Teriparatide,
the recombinant 1–34 fragment of human parathyroid hor-
mone (PTH), enhances bone formation. The drug was li-
censed first by the Food and Drug Administration in the US
(Forteo) and more recently by the European Agency for the
Evaluation of Medicinal Products, for established postmeno-
pausal osteoporosis, the recommended treatment duration
* Corresponding author.
E-mail address: f.debiais@chu-poitiers.fr (F. Debiais).
© 2003 Published by Éditions scientifiques et médicales Elsevier SAS.
doi:10.1016/j.jbspin.2003.08.002
induces bone catabolism, intermittent PTH administration
stimulates bone anabolism. The earliest studies of PTH in
animal models were done in the late 1920s. Uncontrolled
trials in small populations of human patients were conducted
over 20 years ago; they showed an increase in bone mass.
More recently, randomized clinical trials confirmed the ana-
bolic effect of intermittent PTH therapy on bone tissue and
evaluated potential benefits in patients with postmenopausal
osteoporosis.
2. Pharmacology
Human PTH is an 84-amino acid polypeptide involved in
bone remodeling and calcium homeostasis. The biological
activity of PTH is related almost entirely to the first 34 amino
acids counting from the N terminus. Teriparatide is this
34 amino acid segment produced by recombination. Endog-
enous human PTH is rapidly degraded, mainly in the liver
and kidneys. When teriparatide is injected subcutaneously in
a dosage of 20 µg, plasma teriparatide concentrations peak
after about 30 min then drop to undetectable levels within
3–4 h.
466 F. Debiais / Joint Bone Spine 70 (2003) 465–470
3. Mechanisms underlying the anabolic effect
of parathyroid hormone
PTH exerts multiple effects on bone cells [2]. The net
result may be either catabolism or anabolism, according to
the dose and route of administration. In vivo, chronic PTH
administration increases remodeling cycle frequency,
whereas small doses of PTH given intermittently stimulate
bone anabolism. These differences associated with the mo-
dality of administration remain poorly understood. However,
several mechanisms have been suggested [2,3].
3.1. Effects of PTH on signaling pathways in osteoblasts
Osteoblasts and the precursor cells that line bone surfaces
carry PTH receptors; binding of the hormone to its receptor
induces a response that involves a number of second messen-
gers. Two second messenger systems can be activated by
PTH: the G protein pathway, which activates adenylcyclase,
elevates intracellular cyclic AMP (AMPc) levels, and acti-
vates the protein kinases A; and the Gq pathway, which
activates phospholipase C and membrane protein kinase C
(PKC), a mechanism involved in the induction of osteoblas-
tic cell proliferation. Although most of the anabolic effects of
PTH on bone are associated with activation of the
AMPc/protein kinase A pathway, it has been suggested that
the PKC system may be involved in the effects of intermit-
tently administered PTH. Another hypothesis is that the ana-
bolic and catabolic effects of PTH may be mediated by
different receptors.
3.2. Effects of PTH on growth factor production
The increase in osteoblastic cell proliferation induced by
PTH may be related in part to increased production of IGF-I
and its binding proteins, as well as to production of TGF-b, a
growth factor with mitogenic effects on osteoblasts.
3.3. Effects of PTH on the production of RANK-L
and osteoprotegerin
PTH may stimulate RANK-L production by osteoblastic
cell precursors, thereby increasing osteoclast differentiation
and activity. Continuous PTH administration causes an in-
crease in RANK-L and a decrease in osteoprotegerin; when
PTH is given intermittently, in contrast, changes in RANK-L
and osteoprotegerin are short-lived [4] or absent [5], result-
ing in stimulation of osteoblastic effects.
3.4. Effects of PTH on osteoblast apoptosis
PTH decreases osteoblast apoptosis, thereby prolonging
the lifespan of these cells [6].
4. Efficacy of parathyroid hormone in the treatment
of postmenopausal osteoporosis
The earliest studies of PTH in animal models were done in
the late 1920s. Administration of PTH extracts to rodents was
found to increase bone mass. Later, intermittent PTH admin-
istration to rats, dogs, rabbits, and monkeys was reported to
augment bone mass via an increase in cancellous bone, with
either no change or a modest decrease in cortical bone. This
effect improved the mechanical resistance of the vertebras
and femur. The first data in humans came from uncontrolled
trials conducted by Reeve et al. in small patient populations.
In 1976, these authors reported that a 6-month course of PTH
therapy given to four women with osteoporosis induced an
increase in bone turnover with greater bone formation than
bone resorption [7]. In 1980, they described their findings in
21 patients (including 16 women) with osteoporotic fractures
who were given the 1–34 fragment of PTH [8]; increases
were noted in bone trabecular volume and active osteoid
surface. Additional studies in small numbers of patients
evaluated the effects of PTH in combination with another
agent (1,25 dihydroxyvitamin D, estrogens, or calcitonin)
and found gains in trabecular bone mass (in 3). Randomized
clinical trials in larger populations have been conducted
recently in patients with postmenopausal osteoporosis. Most
of them evaluated the 1–34 fragment of human PTH obtained
by recombination (rhPTH(1–34), i.e. teriparatide) or chemi-
cal synthesis; a few used the full 84-amino acid PTH chain
[9,10].
4.1. Studies of PTH alone
4.1.1. Effects of PTH on bone mineral density
A phase II study was conducted in 217 postmenopausal
women with low BMD values (T-score < –2.0) who were
given either a placebo or 50, 75, or 100 µg of rhPTH(1–84)
for 1 year [9,10]. A dose-dependent increase in BMD was
noted at the lumbar spine, the gain being 6.9% in the women
given the highest dosage. No significant changes were re-
corded at the femur, and a slight decline in whole body BMD
was noted. A landmark study by Neer et al. [11] evaluated
daily subcutaneous injections of 20 or 40 µg of rhPTH(1–34)
in 1637 women with fractures due to postmenopausal os-
teoporosis. Supplemental calcium (1000 mg) and vitamin D
(400–1200 IU) was given to all the patients. After a mean
follow-up of 18 months, lumbar BMD increases of 9% and
13% were noted with 20 and 40 µg of rhPTH(1–34), respec-
tively, as compared to the placebo group. Femoral BMD
increased by 3% and 6%, respectively, and whole body BMD
by 2% and 4%. At the radial diaphysis, BMD decreased by
2% in the 40-µg group but showed no significant change in
the 20-µg group, as compared to the placebo; no significant
differences in distal radius values were found among the
three groups.
4.1.2. Effects on vertebral fractures
The incidence of fractures was the primary evaluation
criterion in the study by Neer et al. [11]. This large phase III
trial in 1637 postmenopausal women with at least one verte-
bral fracture showed large fracture risk reduction with
rhPTH(1–34) therapy, of 65% and 69% with 20 and 40 µg,
 F. Debiais / Joint Bone Spine 70 (2003) 465–470
respectively, as compared to the placebo; furthermore, the
risk of experiencing two fractures or more dropped by 77%
and 86%. Among the women who experienced incident ver-
tebral fractures, the mean loss of stature was greater in the
placebo group (–1.1 cm) than in the groups given 20 µg
(–0.2 cm) or 40 µg (−0.3 cm) of PTH. In the same patient
cohort, Marcus et al. [12] looked for a relation between
treatment response and patient age, vertebral BMD, or num-
ber of prevalent fractures. Lumbar BMD showed a larger
increase in the patients older than 65 years, but age had no
influence on the reduction in vertebral fracture risk. Teri-
paratide significantly reduced the vertebral fracture risk in
patients whose T-score was <−3.3 (P < 0.001) or between
–2.1 and –3.3 (P < 0.027) and produced only a trend toward a
reduced fracture risk in patients whose T-score was greater
than –2.1. Teriparatide decreased the risk of incident verte-
bral fractures independently from the number of prevalent
vertebral fractures.
4.1.3. Effects on nonvertebral fractures
In the study by Neer et al [11], incident nonvertebral
fractures related to bone insufficiency occurred in 6% of the
women receiving the placebo and in 3% of those in the two
rhPTH(1–34) treated groups. The risk of experiencing one or
more incident nonvertebral fractures was decreased by 53%
and 54% with the 20 and 40 µg dosages, respectively, as
compared to the placebo group.
4.2. Comparison of the effıcacy of teriparatide
and alendronate
The effects of teriparatide, 40 µg/day, or alendronate,
10 mg/day, given for a mean of 14 months were compared in
146 women with postmenopausal osteoporosis [13]. BMD,
the incidence of nonvertebral fractures, and bone turnover
were the evaluation criteria. Lumbar BMD increased by
12.2% in the PTH group and by 5.6% in the alendronate
group. The BMD increase occurred rapidly in the teriparatide
group (5.2% within the first 3 months). BMD increases at the
femoral neck and whole body were significantly larger with
teriparatide than with alendronate, whereas no difference
was found at the trochanter. Ultradistal radial BMD remained
unchanged in the two groups; distal radial BMD showed no
modifications in the alendronate group but decreased in the
PTH group, both versus the baseline values and versus the
values in the alendronate group. The incidence of nonverte-
bral fractures was lower in the teriparatide group (4.1%) than
in the alendronate group (13.7%); however, the potential role
for trauma was not taken into account, and fractures of the
feet and toes were included. The changes in markers for bone
remodeling reflected the different mechanisms of action of
the two agents: alendronate decreased the bone resorption
marker NTX (urine type I collagen cross-linked telopeptides)
within the first month and the bone formation marker bone
alkaline phosphatase (BAP) within 3 months, by about 50%,
whereas teriparatide increased both markers within 1 month,
467
the highest elevations achieved being 100% for BAP, after
6 months, and 160% for NTX, after 12 months.
4.3. Concomitant treatments
The effects of combining an antiresorptive agent and PTH
have been studied. The two agents were given simulta-
neously or, less often, sequentially to increase or to maintain
the bone mass gain achieved with PTH.
4.3.1. Simultaneous treatment with PTH and a bone
resorption inhibitor
4.3.1.1. Parathyroid hormone and hormone replacement
therapy. The first data on concomitant treatment with PTH
and hormone replacement therapy (HRT) were reported in
1997 by Lindsay et al. [14], who conducted a preliminary
study in 34 patients with postmenopausal osteoporosis. In
2001, Cosman et al. [15] described their findings in
52 women who were given HRT for at least 2 years followed
for the next 3 years by either HRT alone or HRT and a daily
subcutaneous injection of hPTH(1–34) in a dosage of 400 U
(25 µg). All the patients had a calcium intake of at least
1500 mg/day and received 400 IU of supplemental vitamin D
per day. After PTH discontinuation, HRT was continued in
the two groups, which were monitored for an additional year.
In the HRT-only group, BMD and biochemical markers for
bone turnover remained unchanged throughout the 4-year
follow-up. In the HRT plus PTH group, an early increase in
the bone formation marker osteocalcin was noted, followed
after a few months by an increase in the bone resorption
marker NTX [14]. The levels of these markers were greatest
after 6 months, remained high for 18–24 months, and finally
returned to baseline values within 30 months [14,15]. BMD
increased at the spine (13.4 ± 1.4%), total hip (4.4 ± 1.0%),
and whole body (3.7 ± 1.4%); the bone mass increase was
greatest during the first 6–12 months. BMD and biochemical
marker values showed no change during the 1-year follow-up
after PTH discontinuation. As compared to HRT alone, com-
bining PTH and HRT decreased the percentage of women
with vertebral fractures, from 37.5% to 8.3% or from 25% to
0% when a vertebral height loss of 15% or 20% was used to
define vertebral fracture, respectively. Roe et al. [16] re-
ported a randomized double-blind placebo-controlled trial
evaluating the effects of hPTH(1–34), 400 IU/day, in 74 os-
teoporotic women who had been on HRT for at least 1 year;
After 2 years on therapy, the BMD increases were 29.2% and
0.9% at the lumbar spine in the PTH and placebo groups,
respectively; at the femoral neck, BMD increased by 11%
and 0.2% with PTH and the placebo, respectively.
Thus, combining HRT and PTH induces far larger in-
creases in lumbar spine and femoral BMD values than does
HRT alone. Continued HRT maintains the BMD gains in-
duced by PTH for at least 1 year after PTH discontinuation.
Few studies evaluated vertebral fractures. However, data
obtained by Cosman et al. [15] suggest a greater decrease in
468 F. Debiais / Joint Bone Spine 70 (2003) 465–470
the vertebral fracture risk with HRT and PTH than with HRT
alone. Data from a group treated with PTH alone would have
been of interest.
4.3.1.2. PTH and alendronate in combination. Cosman et
al. [17] studied biochemical markers for bone remodeling in
10 women with osteoporosis already treated by alendronate,
10 mg/day. Five patients remained on alendronate therapy
only and the other five received add-on treatment with a daily
subcutaneous injection of hPTH(1–34), 400 IU for 6 weeks.
Bone formation markers increased during the first 3 weeks of
PTH therapy (osteocalcin, 49%; C-terminal propeptide of
type I procollagen (PICP), 61%; and BAP, 24%) and returned
to baseline values after PTH discontinuation, with PICP
showing the steepest decline. No changes occurred in the
alendronate-only group, and bone resorption markers (uri-
nary pyridinoline and NTX) remained unchanged in both
groups during the study period. The results of this study in a
small number of patients suggest that PTH may enhance
bone formation even in the presence of alendronate. This
finding is of interest given earlier data from a study in ewes
suggesting that combining tiludronate to PTH for 3 months
might abolish the osteoblast response to PTH [18].
4.3.1.3. PTH and calcitonin in combination. Hodsman et
al. [19] compared cycles of hPTH(1–34) therapy followed by
calcitonin or a placebo in 30 women with postmenopausal
osteoporosis. A daily injection of hPTH(1–34), 800 U, was
given in cycles of 28 consecutive days separated by 3-month
intervals. Each hPTH(1–34) cycle was followed by either
calcitonin injections (75 U/day) or a placebo, for 42 days.
After 2 years, BMD was increased at the lumbar spine and
unchanged at the femoral neck in the group given hPTH(1–
34) only. Calcitonin did not provide additional benefits.
4.3.2. Sequential treatment with PTH and bone resorption
inhibitors
4.3.2.1. PTH after bone resorption inhibitor therapy. A re-
cent study in ovariectomized rats found that previous long-
term treatment with alendronate, estrogens, or raloxifene did
not delay the bone formation-enhancing effects of teri-
paratide [20]. Ettinger et al. [21] studied the changes in
markers for bone turnover induced by teriparatide therapy
given at completion of at least 18 months of bone resorption
inhibitor therapy in postmenopausal women with osteoporo-
sis. Markers for bone formation (osteocalcin, collagen type I
N-terminal propeptide (PINP), and BAP) and bone resorp-
tion (NTX and type I collagen cross-linked C-telopeptides
(CTX)) increased in response to teriparatide. Bone formation
markers showed two- to threefold larger increases after ral-
oxifene therapy than after alendronate therapy.
4.3.2.2. PTH before alendronate. Sixty-six women with
postmenopausal osteoporosis were treated for 1 year with
either a placebo or a daily injection of PTH(1–84) in a dosage
of 50, 75, or 100 µg. The following year, alendronate was
given in a dosage of 10 mg/day [10]. Lumbar spine BMD
increased during the first year, by 1.3%, 4.3%, 6.9%, and
9.2% with the placebo and the 50, 75, and 100 µg PTH(1–84)
dosages, respectively; corresponding increases during the
following year were 5.7%, 6.3%, 6.2%, and 4.9%. After
2 years on treatment, lumbar spine BMD increases in the
placebo group and 50, 75, or 100 µg PTH(1–84) groups were
7.1 ± 5.3%, 11.3 ± 5.7%, 13.4 ± 5%, and 14.6 ± 7.9%; these
BMD gains were larger than in studies where bone resorption
inhibitors were used alone. Thus, alendronate maintained the
lumbar spine BMD gains provided by PTH therapy and
induced an additional BMD increase similar in magnitude to
that obtained in patients given alendronate without PTH. At
the femoral neck, BMD showed no changes versus baseline
values within the groups or across the groups; after 2 years,
however, femoral neck BMD increases of 4.2%, 5.5% 5.8%,
and 4.5% were found, and the gains were significant with the
50 and 75 µg PTH(1–84) dosages. Whole body measure-
ments showed a significant BMD decrease after 1 year of
treatment with 75 or 100 µg of PTH as compared to the
placebo; after 2 years, in contrast, BMD was increased in all
the groups, with no significant differences across groups.
These data establish that previous treatment with PTH does
not impair subsequent responses to alendronate during the
second year. However, this study did not include a placebo
group without alendronate therapy, and it is difficult to evalu-
ate the results of the anabolic effect of PTH(1–84) after
discontinuation of this agent. The ability of a bone resorption
inhibitor to maintain BMD gains provided by PTH depends,
however, on the potency and dosage of the inhibitor. In a
study of sequential therapy with PTH followed by clodronate
(400 mg/day for 1 month at 3-month intervals), clodronate
failed to maintain the BMD gains provided by PTH [22].
4.4. Bone biopsy data
Bone biopsies obtained before and after PTH therapy in
women with postmenopausal osteoporosis showed that PTH
induced a significant increase in trabecular bone volume
[8,23]. Other studies found an increase in cortical bone thick-
ness with no change in cortical porosity [24,25]. Further-
more, analysis of three-dimensional microtomographies of
iliac bone biopsies demonstrated improvements in bone ar-
chitecture with an increase in trabecular connectivity [25].
PTH promotes periosteal bone formation and bone size. In
the study by Neer et al [11], peripheral quantitative computed
tomography was used in a subgroup of patients to examine
parameters at the distal radius. The results showed increases
in bone mineral content, cortical bone surfaces, total bone
surfaces, periosteal bone circumference, and endocortical
bone circumference [26].
5. Safety
The main side effects recorded in the study by Neer et al.
[11] were nausea and headaches occurring in a dose-
 F. Debiais / Joint Bone Spine 70 (2003) 465–470
dependent manner, vertigo, and cramps. Another side effect
was hypercalcemia, which was usually moderate and short-
lived. Serum calcium levels greater than 2.6 mmol/l were
found in 2% of the placebo group patients, 11% of the 20-µg
PTH group patients, and 28% of the 40-µg PTH group pa-
tients; however, in 95% of patients with hypercalcemia, se-
rum calcium levels remained under 2.80 mmol/l in the 20 µg-
group and under 2.95 mmol/l in the 40 µg-group, and
persistent hypercalcemia occurred in only 3% and 11% of the
patients in these two groups, respectively. No differences
were noted between the placebo and treated groups regarding
the number of deaths or of patients with cardiovascular
disease, renal lithiasis, or gout. No evidence of interaction
with digoxin was found in a recent study [27]. Osteosarcoma
development has not been reported in studies in humans.
However, several clinical studies were stopped prematurely
because a study of carcinogenic potential found an increased
rate of osteosarcoma development in Fisher rats [28]. It is
important to note that the rats received high-dose PTH
throughout their entire life. No increase in osteosarcomas
was found in monkeys. In patients with primary hyperpar-
athyroidism, presence of osteosarcoma has been noted in
only four women [29].
6. Conclusion
Studies in postmenopausal osteoporosis have confirmed
that PTH(1–34) exerts anabolic effects on bone and provides
a large reduction in the fracture risk. The role for teriparatide
in the management strategy for osteoporosis remains to be
defined. Further work is also needed to determine whether
teriparatide is best used alone or in combination with bone
resorption inhibitors. Sequential regimens may hold prom-
ise. Ongoing studies [21,30,31] are evaluating the amount of
bone lost after PTH discontinuation, the potential usefulness
of bone resorption inhibitors for maintaining bone mass
gains provided by PTH therapy, and the possible benefits of
combination treatments in decreasing the fracture risk.
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