Sequential Parathyroid Hormone/Alendronate Therapy for OsteoporosisRobbing Peter to Pay Paul?
Mara Horwitz,
Andrew Stewart and
Susan L. Greenspan
University of Pittsburgh Medical Center
Division of Endocrinology and Metabolism
Pittsburgh, Pennsylvania 15213
Address correspondence and requests for reprints to: Susan L. Greenspan, M.D., University of Pittsburgh Medical Center, Osteoporosis Prevention and Treatment Center, 1110 Kaufmann Building, 3471 Fifth Avenue, Pittsburgh, Pennsylvania 15213. E-mail:
greenspans{at}msx.dept-med.pitt.edu
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Introduction
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Although we currently have multiple Food and Drug
Administration-approved antiresorptive therapies for the treatment of
postmenopausal osteoporosis, the gains in vertebral bone mass approach
only 67% over 3 yr with single-agent antiresorptive therapy (1, 2, 3)
and up to 89% over 3 yr with two antiresorptive agents given
simultaneously (4). Because bone mass has often decreased an average of
30% when postmenopausal women experience fractures and greater
increases in bone mass are associated with greater vertebral fracture
reduction (5), investigators have, therefore, searched for an ideal
agent(s) to increase bone formation while suppressing or maintaining
the rate of bone resorption. Previous studies have shown that
PTH stimulates both bone formation and resorption with a greater
net impact on bone formation, resulting in an increase in bone mass,
particularly in trabecular bone (6). However, the "presentation" of
PTH is crucial. When PTH is given as a constant infusion to animals or
in disease states such as hyperparathyroidism where the levels are
constantly elevated, the result is a loss of bone, especially at
cortical sites (6, 7, 8). In contrast, like many other endocrine systems,
when the hormone is presented in a pulsatile or intermittent fashion,
it stimulates a net increase in bone mass at mainly trabecular sites.
However, one concern with the anabolic agent PTH, when given as an
intermittent injection, has been the potential trade-off of "robbing
Peter to pay Paul." Several studies involving PTH treatment have
shown either a maintenance or loss of cortical bone at some sites in
comparison with improvements in vertebral bone mass, or trabecular bone
(9, 10, 11, 12), which may be related to an increase in the remodeling space
(6). This is a critical issue because if bone mass is only maintained,
potentially lost, or placed in a more fragile and biomechanically
insecure state at clinically relevant cortical sites, hip fractures may
not be reduceda much more costly and morbid event than vertebral
fractures. However, lack of vitamin D sufficiency in patients at
baseline or differences between PTH(1-34) and PTH(1-84) absorption,
carriers, and circulating time may contribute to observed differences
in cortical bone. A second concern is that, following discontinuation
of anabolic therapy with PTH, patients may then lose bone and return to
their previous baseline after withdrawal of therapy (9).
The study by Rittmaster et al. (13) suggests a possible
solution to several of these concerns. At the conclusion of a 1-yr,
double-blind, placebo-controlled study in postmenopausal women with
daily sc injections of PTH(1-84) at three doses (50, 70, and 100 µg)
vs. placebo, a small subset of patients (n = 75) were
treated with 10 mg open-label alendronate daily for the following year.
Patients received 500 mg supplementary calcium and 400 IU vitamin D.
After the 1st year of PTH therapy, there were no significant changes in
femoral neck bone mineral density (BMD) accompanied by decreases of
3.5% and 2.8% in total body bone mass in the patients who received
the two highest doses of PTH, along with increases of 6.9% and 9.2%
at the spine. Given the low turnover of cortical bone at the hip,
changes at the total hip or femoral neck may not be observed in 1 yr,
especially in a small cohort. However, patients treated with several
antiresorptive agents in large clinical trials have demonstrated
improvements at the hip after only 1 yr (2, 3, 14). The investigators
observed further increases of up to 14% in spinal bone mass during the
subsequent year of treatment with alendronate in the group that had
previously received the highest dose of PTH. Although they observed a
trend in improved hip bone mass compared with baseline, this was not
statistically significant at two of the doses of PTH, including the
highest dose after 2 yr of this sequential therapy. Whole body BMD
(primarily composed of cortical bone) did improve compared with
baseline in three of four groups after the year of alendronate therapy.
Therefore, whereas the sequential anabolic therapy, followed by
antiresorptive therapy, was able to improve the total body bone mass in
the highest dose, there was no significant gain in hip BMD at this same
dose. The sequential therapy did, however, halt further loss of
cortical bone and resulted in further improvement in trabecular bone at
the spine. Alternatively, the reversal of cortical bone loss may also
be dependent on the duration of PTH therapy. In a study with women who
were estrogen deficient from GnRH therapy, Finkelstein et
al. (12) observed significant losses at the femoral neck and hip
trochanter after 6 months of PTH therapy. However, by 12 months PTH
therapy prevented loss from the proximal femur (15). Because the number
of participants in the open-label extension was small, the authors did
not observe a consistent effect at all doses and sites. Therefore,
although the trends are encouraging, we do not know whether we have
paid off Peter, or if sequential therapy of PTH, followed by
alendronate, is more advantageous than a single antiresorptive agent
that could significantly improve hip bone mass after 2 yr (14).
Other studies have shown that the combination of simultaneous hormone
replacement therapy (HRT) and PTH (or PTH added to women who are on
HRT) provides further increases in spine, total body, and hip BMD (16, 17). Furthermore, Lindsay et al. (16) noted a reduction in
vertebral fractures (assessed as a 15% decrease in vertebral height).
Although the study by Rittmaster et al. (13) was not powered
to examine reduction in vertebral fractures, the outcomes of concern
are still fracture reduction. A combination of simultaneous anabolic
and antiresorptive therapy may be a better pattern of therapy if it
results in significant gains at both the spine and the hip with trends
for fracture reduction.
This study is important because it lends further support to the ongoing
body of evidence about the role of combination therapy for the
treatment of osteoporosis. The study shows the success of sequential
therapy for greater improvements in vertebral bone mass, prevention of
bone loss following therapeutic withdrawal of PTH, and reversal of
cortical bone loss. However, further research is needed to demonstrate
improvement in hip bone mass with this kind of sequential therapy, with
the goal that such therapy would ultimately be associated with
reduction in hip fractures. This study also lays the foundation for
examination of simultaneous anabolic and antiresorptive therapy with
this combination of PTH and bisphosphonate. Furthermore, the clinical
implications suggest that a potential future treatment for osteoporosis
may consist of baseline continuous antiresorptive therapy with agents
such as HRT, selective estrogen receptor modulators, or
bisphosphonates, with an intermittent bolus of an anabolic therapy like
PTH to improve bone mass further and potentially reduce fractures. The
next step is the examination of biomechanical strength and a
larger-scale clinical trial of combination therapy powered to assess
fractures as an end point. We have previously witnessed the fallout
from fluoride (18, 19), another anabolic agent, which resulted in a
significant increase in bone mass that was biomechanically inferior and
resulted in an increase in vertebral fractures. Because fracture
outcome and, most importantly, hip fracture reduction are the ultimate
targets for osteoporosis treatment, we need to ensure that new anabolic
therapy or combinations of anabolic and antiresorptive therapies are in
a pattern simultaneously rewarding Peter and Paul.
Received March 20, 2000.
Accepted April 5, 2000.
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