0163-769X/05/$20.

00/0 Endocrine Reviews 26(5):688 –703

Printed in U.S.A. Copyright © 2005 by The Endocrine Society
doi: 10.1210/er.2004-0006

Parathyroid Hormone and Teriparatide for the

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Treatment of Osteoporosis: A Review of the Evidence
and Suggested Guidelines for Its Use
Anthony B. Hodsman, Douglas C. Bauer, David W. Dempster, Larry Dian, David A. Hanley, Steven T. Harris,
David L. Kendler, Michael R. McClung, Paul D. Miller, Wojciech P. Olszynski, Eric Orwoll, and Chui Kin Yuen
Department of Medicine (A.B.H.), University of Western Ontario, London, Ontario, Canada N6A 4V2; Department of
Medicine, Epidemiology, and Biostatistics, Division of Medicine (D.C.B.), University of California, San Francisco, California
94105-3411; Department of Pathology (D.W.D.), Columbia University, New York, New York 10027-6902; Regional Bone
Center (D.D.), Helen Hayes Hospital, West Haverstraw, New York 10993; Division of Geriatric Medicine (L.D.), University of
British Columbia, Vancouver, British Columbia, Canada V6T 2B5; Division of Endocrinology and Metabolism, Department
of Medicine (D.A.H.), University of Calgary, Calgary, Alberta, Canada T2N 4N1; Department of Medicine (S.T.H.),
University of California, San Francisco, California 94117-3619; Department of Medicine and Endocrinology (D.L.K.),
Osteoporosis Research Centre, University of British Columbia, Vancouver, British Columbia, Canada V5Z 2N6; Oregon
Osteoporosis Center and Department of Medical Education (M.R.M.), Providence Portland Medical Center, Portland, Oregon
97213; Department of Medicine, University of Colorado Medical School, and Colorado Center for Bone Research (P.D.M.),
Lakewood, Colorado 80227; Department of Medicine, University of Saskatchewan, and Saskatoon Osteoporosis Centre
(W.P.O.), Saskatoon, Saskatchewan, Canada S7K 0H6; Department of Medicine and General Clinical Research Centre
(E.O.), Oregon Health & Sciences University, Portland, Oregon 97201-3079; and Department of Obstetrics, Gynecology, and
Reproductive Sciences, University of Manitoba, and Manitoba Clinic (C.K.Y.), Winnipeg, Manitoba, Canada R3A 1M3

All therapies currently recommended for the management of dividuals at particularly high risk for fractures, including
osteoporosis act mainly to inhibit bone resorption and reduce subjects who are younger than age 65 and who have partic-
bone remodeling. PTH and its analog, teriparatide [recombi- ularly low bone mineral density measurements (T scores <
nant human PTH(1–34)], represent a new class of anabolic 3.5). Teriparatide therapy is not recommended for more than
therapies for the treatment of severe osteoporosis, having the 2 yr, based, in part, on the induction of osteosarcoma in a rat
potential to improve skeletal microarchitecture. Significant model of carcinogenicity.
reductions in both vertebral and appendicular fracture rates Total daily calcium intake from both supplements and di-
have been demonstrated in the phase III trial of teriparatide, etary sources should be limited to 1500 mg together with ad-
involving elderly women with at least one prevalent vertebral equate vitamin D intake (<1000 U/d). Monitoring of serum
fracture before the onset of therapy. However, there is as yet calcium may be safely limited to measurement after 1 month
no evidence that the antifracture efficacy of PTH will be su- of treatment; mild hypercalcemia may be treated by with-
perior to the bisphosphonates, whereas cost-utility estimates drawing dietary calcium supplements, reducing the dosing
suggest that teriparatide is significantly more expensive. frequency of PTH, or both. At present, concurrent therapy
Teriparatide should be considered as treatment for post- with antiresorptive therapy, particularly bisphosphonates,
menopausal women and men with severe osteoporosis, as well should be avoided, although sequential therapy with such
as for patients with established glucocorticoid-induced osteo- agents may consolidate the beneficial effects upon the skel-
porosis who require long-term steroid treatment. Teripa- eton after PTH is discontinued. (Endocrine Reviews 26:
ratide should also be considered for the management of in- 688 –703, 2005)

I. Introduction B. Structural changes in bone after PTH therapy

II. Biological Activity of PTH V. Clinical Trials with Teriparatide and Intact PTH
III. Antiresorptive Therapy A. Teriparatide
A. Bisphosphonates B. Trials with intact PTH
B. Other antiresorptive agents VI. Side Effects and Precautions
IV. Anabolic Therapy A. Hypercalcemia and hypercalciuria
A. Mechanism of action: anabolic vs. antiresorptive therapy B. Osteosarcoma
C. Additional precautions
First Published Online March 15, 2005 VII. PTH in Clinical Practice
Abbreviations: BMD, Bone mineral density; C, carboxyl; DXA, dual A. Candidates for PTH therapy
x-ray absorptiometry; GIOP, glucocorticoid-induced osteoporosis; intact
B. Monitoring
PTH, intact or full sequence PTH(1– 84); QCT, quantitative computed
tomography. C. Duration of therapy
D. PTH and cotherapy with antiresorptive agents
Endocrine Reviews is published bimonthly by The Endocrine Society
(http://www.endo-society.org), the foremost professional society serv- VIII. Summary
ing the endocrine community. IX. Recommendations

688
Hodsman et al. • PTH Therapy for Osteoporosis Endocrine Reviews, August 2005, 26(5):688 –703 689

I. Introduction acids are obligatory for biological activity, and it appears that
the bone anabolic properties are fully maintained by the
P TH AND ITS analogs represent a new class of anabolic
agents for the treatment of severe osteoporosis, unlike
currently licensed therapies to manage osteoporosis, which
foreshortened fragment hPTH(1–31) or its cyclized lactam.
Although the 84-amino acid intact PTH is the natural product

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act primarily to inhibit bone resorption and remodeling. In of PTH gene transcription and translation, the major immu-
this paper members of the Western Osteoporosis Alliance noreactive circulating PTH species consists of carboxyl (C)-
have reviewed the clinical literature, published between 1990 terminal fragments of the hormone. These fragments are
and June 2004 —the period of active development of the secreted by the parathyroid cell, with intracellular cleavage
therapeutic use of these agents for the therapy of osteopo- enhanced by elevated extracellular fluid calcium (3). They
rosis. In addition to a search of Medline, with particular also arise from cleavage of intact PTH by peripheral (target)
attention to controlled clinical trials, the important English tissues (4). N-terminal residues capable of receptor activation
language bone and specialty journals were hand searched for do not exist in the circulation under normal physiological
the most recent publications in the clinical field of PTH conditions; after target tissue receptor binding, amino-
therapy. A full historical review of the clinical and experi- terminal fragments may be formed, which are then rapidly
mental evidence was neither appropriate nor necessary to degraded. The only known circulating form with biological
arrive at current consensus. Grades of evidence were as- activity at the PTH/PTHrP receptor is the full-sequence in-
signed according to the published criteria for developing tact PTH(1– 84) peptide.
clinical guidelines (1). Randomized clinical trials in which It is possible that C-terminal fragments of intact PTH may
there was an appropriate control group would consistently have discrete biological properties. Both in vitro and in vivo
lead to consensus recommendations of grade A or B. Of the studies indicate that the C-terminal part of PTH may have
four grades attached to our recommendations, grade D rep- significant biological effects in bone. Evidence is accumulat-
resents consensus expert opinions because there are many ing that a separate receptor for the C terminus of PTH exists.
areas in which there are no data from randomized controlled Bringhurst and associates (5) have demonstrated that C-PTH
clinical trials. Data published in abstract form are identified fragments may enhance osteocyte apoptosis, and earlier cell
as such in the reference section, and are included when it culture studies of osteoblasts have shown that C-terminal
seemed necessary to add to the body of information about fragments containing at least the last 30 or more amino acids
mechanisms of action or therapeutic response. Table 1 de-
of PTH will stimulate production of alkaline phosphatase
scribes the levels of evidence and grades of recommenda-
and other markers of osteoblast activity (6). It is therefore
tions with which we have arrived at suggested guidelines for
plausible that intact PTH, when used as a therapy for os-
the use of PTH in managing osteoporosis.
teoporosis, may have slightly different biological actions
compared with teriparatide.
II. Biological Activity of PTH PTH exhibits potent anabolic effects on the skeleton when
given exogenously by intermittent injection. This was first
Human PTH is an 84-amino acid peptide that plays a reported in humans by Reeve et al. (7) in 1980. In this study
central role in the maintenance of calcium homeostasis in
a small group of patients received teriparatide by daily sc
mammals (2). The ambient extracellular calcium level signals
injections for 6 –24 months. Paired bone biopsies revealed
an increase in PTH secretion in response to a decrease in
substantial increases in iliac trabecular bone volume, with
calcium concentration via the calcium-sensing receptors on
evidence of new bone formation and a suggestion that there
the parathyroid cellular membrane. PTH acts directly to in-
crease renal tubular calcium reabsorption and indirectly to was a dissociation between bone formation and resorption
enhance intestinal calcium absorption via its stimulatory ac- rates. Numerous historical studies have consistently con-
tion on renal 1-␣ cholecalciferol hydroxylase (thereby in- firmed improvements in bone tissue after daily injections of
creasing circulating calcitriol). The normal physiological role PTH analogs (8), but only recently has teriparatide become
of PTH on skeletal homeostasis, when secreted endog- commercially available. The molecular mechanisms by
enously, is more complex but probably serves to regulate which PTH analogs result in a partial reconstruction of skel-
bone remodeling rather than overall skeletal mass. etal architecture in subjects with severe osteoporosis are as
From early structure-function studies of PTH, it has been yet unclear (2). However, a review of the recent literature
generally assumed that all of the biological activity of intact supports the observation that architectural improvements do
PTH (hPTH 1– 84) resides in the N-terminal sequence; most occur within the skeleton after daily PTH injections. This is
clinical studies have used the 34-amino acid peptide in contrast to changes in the skeletal architecture observed
hPTH(1–34), now named teriparatide. The first two amino after therapy with antiresorptive agents, which act mainly by

TABLE 1. Grades of recommendation for clinical practice guidelines (1)

Grade Criteria
A One or more randomized controlled trial(s) with adequate power, or metaanalysisa
B Randomized controlled trial(s) not meeting all criteria for grade Aa
C Nonrandomized trial(s) or cohort studies, plus consensus
D Any lower level of evidence supported by consensus (including expert opinion)
a
An appropriate level of evidence was necessary but not sufficient to assign a grade of recommendation; consensus was required in addition.
690 Endocrine Reviews, August 2005, 26(5):688 –703 Hodsman et al. • PTH Therapy for Osteoporosis

reducing bone turnover and preserving, rather than improv- has been shown to reduce the risk for appendicular fractures.
ing, skeletal architecture. By comparison with bisphosphonates, the increments in
BMD seen with other antiresorptive agents are more modest.
All clinical trials evaluating the use of treatment for osteo-

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III. Antiresorptive Therapy porosis have included nutritional supplements of calcium
Most forms of osteoporosis are a consequence of bone loss and vitamin D to both the placebo and treatment arms. Very
due to an imbalance in bone remodeling such that bone low intakes of calcium or impaired calcium absorption due
resorption exceeds bone formation. By decreasing the num- to inadequate vitamin D stores are associated with increased
ber, activity, and life span of osteoclasts, several therapeutic rates of bone loss and increased rates of fracture risk, espe-
agents suppress bone resorption and, indirectly, bone for- cially in the elderly who are less able to adapt to low calcium
mation. These antiresorptive agents are capable of preserv- intake because of age-related inefficiencies in vitamin D me-
ing bone mass, stabilizing bone structure and quality, and tabolism (30). The administration of calcium and/or vitamin
reducing fracture rates. Before the availability of PTH, all of D to elderly adults deficient in these nutrients slowed bone
our therapies for the prevention and treatment of osteopo- loss and reduced the risk of vertebral and nonvertebral frac-
rosis fell into this category. There is an extensive literature tures, including hip fractures (31–34). Thus, effects attributed
both from well-designed clinical trials and several years of to antiresorptive agents are in addition to the effects due to
experience with their use in a clinical setting. calcium and vitamin D alone. Whereas calcium and vitamin
D are important aspects of treatments, pharmacological ther-
apy provides more effective protection from fracture; this is
A. Bisphosphonates probably true for both antiresorptive and anabolic agents.
Bisphosphonates are potent selective inhibitors of oste- Thus, clinicians now have an effective group of antire-
oclastic bone resorption. Both alendronate and risedronate sorptive agents for patients with, or at risk for, osteoporosis.
reduce the incidence of vertebral fractures by 40 –50% in It is against this proven background that the utility of PTH
women known to have osteoporosis (9 –14), with similar and its analogs must be contrasted.
reductions in nonvertebral fractures (15). Both agents have
been shown specifically to reduce the risk of hip fractures by
40 – 60% in women with severe osteoporosis (16, 17). Clinical IV. Anabolic Therapy
trials involving men and patients with glucocorticoid- A. Mechanism of action: anabolic vs. antiresorptive therapy
induced osteoporosis (GIOP), have shown that bisphospho-
nates confer similar benefits in improved bone mineral den- The cellular mechanism of action of PTH is fundamentally
sity (BMD) and reduced vertebral fracture risk (18 –21). different from that of antiresorptive agents. The latter can be
The onset of bisphosphonate action is rapid. Indices of more aptly termed “antiremodeling agents” because, al-
bone resorption were suppressed and occurred within a few though their initial action is to inhibit resorption, they also
weeks of beginning treatment, and the risk of radiological or rapidly inhibit formation, which under most circumstances
vertebral fracture was reduced as early as 6 –12 months (13, is tightly coupled to resorption. Indeed, inhibition of remod-
17, 22). All studies clearly demonstrate improvements in eling is one of the primary mechanisms through which this
BMD during bisphosphonate therapy. However, histomor- class of drugs operate. A decrease in the remodeling rate has
phometric studies obtained during the phase III clinical trials several effects that are beneficial to bone strength, including:
show few differences in trabecular bone architecture com- 1) an improvement in bone density through a decrease in the
pared with patients treated with placebo (23, 24). In the size of the remodeling space; 2) preservation of cancellous
absence of improved trabecular microarchitecture, the incre- bone architecture; 3) a reduction in the number of resorption
ments in BMD are most likely due to enhanced secondary cavities, which act as mechanical stress concentrators with
mineralization of preformed osteons (25). Suppression of the potential to trigger mechanical failure; 4) an increase in
bone resorption allows closure of the existing skeletal re- the amount of bone mineral per unit volume of bone tissue;
modeling space, further enhancing the increments in BMD and 5) a decrease in cortical porosity (25, 35–37).
compared with placebo treatment. Although the negative
balance in the basic multicellular unit is reduced because of B. Structural changes in bone after PTH therapy
shallower resorption cavities during remodeling, there is no
consistent evidence that these drugs eliminate the negative By contrast, PTH stimulates bone formation through an
bone balance or render it positive, so that the apparent in- increase in the bone remodeling rate. Under the influence of
crease in measured bone mass is limited to the reduction of exogenous PTH treatment, the amount of bone laid down in
the reversible remodeling space (26). each remodeling unit, as assessed by osteon thickness, is
increased (38 – 40). This distinguishes the effects of PTH treat-
B. Other antiresorptive agents ment from other high-remodeling states, such as estrogen
deficiency, which are deleterious to bone strength. The com-
Other antiresorptive agents with proven antifracture effi- bination of an increase in the remodeling rate and in the
cacy include long-term estrogen therapy (27), raloxifene (28), amount of bone laid down in each remodeling transaction
and nasal calcitonin (29). In general, the vertebral fracture provides a mechanism for ongoing gains in the amount of
risk reduction has been more variable, but is not generally in bone tissue, including an increase in trabecular thickness
excess of 40%, whereas neither raloxifene nor nasal calcitonin (38), which is not seen with antiresorptive agents, at least
Hodsman et al. • PTH Therapy for Osteoporosis Endocrine Reviews, August 2005, 26(5):688 –703 691

not at the iliac crest. In addition to stimulation of bone for- offset by an increase in both cortical thickness and diameter
mation through this mechanism, which can be referred to as due to new periosteal bone apposition. Such improvements
“remodeling-based formation,” there is also biochemical and in cortical bone architecture with teriparatide treatment are
histomorphometric evidence that teriparatide is initially able now beginning to be documented in humans using a variety

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to uncouple formation from resorption, stimulating forma- of techniques, including histomorphometry (40, 46), periph-
tion directly without a requirement for prior resorption (41– eral quantitative computed tomography (QCT) (58 – 61), ra-
43). This can be referred to as modeling-based formation. diogrammetry (62), and absorptiometric assessment of bone
This may occur by activation of lining cells on previously size (63, 64). Thus, Zanchetta et al. (59) compared cortical
quiescent bone surfaces (44), as well as by osteoblasts en- architecture in the distal radius by peripheral QCT, after 18
gaged in remodeling-based formation migrating outside the months of treatment with teriparatide or placebo. During
borders of the bone remodeling unit to deposit bone on sites teriparatide therapy, new periosteal apposition occurred, but
that were untouched during the resorptive phase of the cycle cortical thickness was unchanged because of concurrent en-
(45). docortical remodeling. However, the greater radial outer
Teriparatide treatment has been shown not only to in- dimension resulted in biomechanically stronger bone as as-
crease trabecular thickness but also to increase trabecular sessed by axial and polar moments of inertia. Similar findings
connectivity as assessed in three dimensions by microcom- have recently been reported for the femoral neck (61). An
puted tomography of iliac crest bone biopsies (40, 46). This increase in the bone formation rate, determined by tetracy-
is shown clearly in Fig. 1. The underlying mechanism is cline labeling, has been reported on the periosteal surface of
uncertain but could involve the initial thickening of trabec- iliac cortical bone in patients treated for only 1 month with
ulae followed by intratrabecular tunneling (47); it is in sharp teriparatide, providing a plausible mechanism for periosteal
contrast to the mechanism of bisphosphonate action, during expansion (43) .
which preservation, rather than alteration, of trabecular ar- That PTH may be able to increase bone size is significant,
chitecture occurs (24). given that the strength of a cylinder is proportional to the
Since the landmark study by Reeve et al. (7), there have fourth power of its radius. Small increments in bone size
been concerns that at least some of the gains in cancellous therefore may have disproportionately greater effects on
bone may be achieved at the expense of cortical bone. Several bone strength. Bone size increases with age, and this com-
clinical studies have demonstrated small decreases in areal pensates for the age-related loss of bone tissue (65– 67). PTH
BMD [measured by dual x-ray absorptiometry (DXA)] at treatment appears to accelerate this natural process. The
cortical bone sites with both teriparatide (48 –52) and intact 20-yr-old belief that intermittent PTH treatment may have
PTH (53). This is likely due to enhanced intracortical remod- deleterious effects on cortical bone therefore appears to be
eling and is self-limiting. Iliac crest bone biopsies do not losing ground. With that comes the realization that to assess
show enhanced cortical porosity after 18 –36 months of the effects of PTH treatment in a clinical setting, we need to
teriparatide treatment (39, 40, 46). Animal data demonstrate exercise caution in interpreting BMD changes, particularly
increased remodeling in the inner two thirds of the cortex, areal measurements provided by DXA. Indeed, BMD mea-
leading to “trabecularization” of the endocortical envelope. surement may give misleading results; a decrease in BMD
Similar active remodeling is seen along endocortical bone in due to enhanced cortical remodeling may not indicate loss of
iliac crest biopsies after teriparatide treatment of postmeno- bone strength if it is accompanied by improvements in cor-
pausal women (39). However, expansion of the inner diam- tical, as well as trabecular, architecture. A further reason that
eter of tubular bone due to this endocortical activity has little areal DXA may underestimate improvement in bone mass
effect on calculated bending strength (54 –57). The effects are lies in the increased volume of relatively undermineralized
osteoid, which occurs when bone turnover is increased. This
is the opposite of the mechanism seen during bisphospho-
nate use and has been documented in paired iliac crest bi-
opsies before and after teriparatide use (68). There is there-
fore a pressing need to explore the utility of other imaging
modalities, such as structural analysis by DXA (69), QCT (70,
71), and high-resolution magnetic resonance imaging (72–74)
in the noninvasive assessment of the effects of PTH on tra-
becular and cortical bone. Development of better surrogate
measures for bone strength will become increasingly impor-
tant for assessing the effects of antifracture drugs, both an-
tiresorptive and anabolic, as fracture trials become progres-
sively more difficult to conduct for practical and economic
reasons.
FIG. 1. Reconstructed micro-QCT images of transiliac crest bone bi- In conclusion, PTH represents the first in a new class of
opsies, taken before and after 21 months of teriparatide therapy, 20 bone anabolic agents. It is the first antifracture drug that has
␮g/d. These images demonstrate increased trabecular thickness and been shown to increase osteoblast number and activity, to
connectivity, together with increased cortical thickness. [Reproduced
with permission from Y. Jiang et al.: J Bone Miner Res 18:1932–1941, increase the bone remodeling rate as well as the amount of
2003 (46) with permission of the American Society for Bone and bone deposited in each remodeling cycle, to increase trabec-
Mineral Research.] ular thickness and improve trabecular connectivity, to stim-
692 Endocrine Reviews, August 2005, 26(5):688 –703 Hodsman et al. • PTH Therapy for Osteoporosis

ulate bone formation without prior resorption, and to in- was no clear distinction of fracture risk reduction between
crease cortical thickness and bone size. the two doses of teriparatide. Moreover, post hoc analysis in
this cohort demonstrated that the fracture risk reduction was
largely independent of age, initial BMD, and prevalent ver-

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V. Clinical Trials with Teriparatide and Intact PTH tebral fractures at baseline (79).
Where fracture incidence data were provided in the other
Table 2 describes the published randomized clinical trials
trials, the numbers of treated patients were too small to
published since 1997. The table describes only those trials
achieve significance; however, there is a consistent trend to
that included both a representative sample of “at risk” sub-
fewer vertebral and nonvertebral fractures in every case (42,
jects and a control not receiving PTH. Whereas the table
78). Body et al. (49) compared teriparatide treatment (40
differentiates studies carried out in postmenopausal women,
␮g/d) [a dose chosen before the study of Neer et al. (50)
men, postmenopausal women with GIOP, and premeno-
suggested 20 ␮g/d as being the most suitable dose], to stan-
pausal women with acute estrogen deficiency, our brief re-
dard therapy with alendronate (10 mg/d) over a median of
view of the evidence describes the overall benefits of PTH
14 months. There was a significant reduction in nonvertebral
therapy irrespective of treatment cohorts; treatment effects
fractures compared with treatment with alendronate (4 vs.
are quite consistent between studies, and we have high-
14%), but some of these may have been traumatic, and the
lighted only the inconsistencies.
absolute numbers were very small (e.g., toe fractures in the
alendronate group are of uncertain significance).
A. Teriparatide
1. Changes in biochemical markers of bone turnover. PTH is a 3. Changes in BMD. PTH consistently increases BMD (mea-
direct anabolic agent in bone tissue. It induces new bone sured by DXA) in predominantly trabecular bone (lumbar
formation on otherwise quiescent bone surfaces, while also spine) and to a lesser degree over a mixed cortical/trabecular
stimulating bone turnover by the classic remodeling cycle site (femoral neck), but has little effect over a mainly cortical
involving both osteoclastic resorption and osteoblastic ref- site (distal radius) where the measured BMD may actually
ormation. Not surprisingly, biochemical markers of both fall slightly. The effect is dose dependent (50, 51, 53, 80) and,
bone formation and resorption increase dramatically and can by comparison to alendronate, of significantly greater mag-
be detected in both blood and urine. Hodsman et al. (75) first nitude (49). Increments in BMD are maximal during the first
showed these increments to occur very early on, within 28 d 18 months of therapy, but the incremental rate may decline
of initiating teriparatide therapy. These findings have been beyond this point (49, 76); however, there are studies in
shown in many studies with teriparatide (42, 48, 49, which the increments in BMD continue to be linear at or after
51, 76 –78) and for intact PTH (53). Increments in markers of 18 months duration of therapy (42, 48). Typically, BMD of the
bone formation (e.g., bone-specific alkaline phosphatase, N- lumbar spine increases from 10 –14% over 1–3 yr (Table 2). In
propeptide of type 1 collagen, osteocalcin) and markers of the phase III teriparatide trial, in which postmenopausal
bone resorption (e.g., urinary N-telopeptide, urine deoxy- women were treated for a median of 19 months, the mean
pyridinoline, serum C-terminal telopeptide) of at least 100% increment in lumbar spine BMD in the group receiving 20
are seen, and, characteristically, bone formation markers in- ␮g/d was 9.7%, vs. 1.1% for placebo-treated patients (50).
crease more rapidly and earlier during the course of therapy Post hoc analysis demonstrated that in 96% of individuals
than those reflecting bone resorption. This may reflect the there was an increase at least above baseline, and in 72% the
direct early anabolic effects of PTH, which is occurring before increase was at least 5% (81).
the bone-remodeling cycle accelerates. Another feature of In contrast, changes in femoral neck BMD are usually less
these bone turnover profiles is a tendency for the increments than 5% over comparable time periods. Changes in BMD
to peak during the first 12 months of therapy but to gradually over the distal radius have been inconsistent through the
decline toward baseline over the next 12–24 months. It is not historical small trials of PTH, but in the more recent con-
known whether this represents a form of tachyphylaxis to trolled clinical trials, it is apparent that PTH results in a
PTH peptides, resulting in diminishing skeletal response consistent small reduction in radial BMD (in the order of
over time. 1–2%) (48 –51). The significance of the apparently adverse
effect on BMD of the distal radius is controversial. The study
2. Reduction in fracture risk. In the phase III trial of teriparatide, by Neer et al. (50) was the only trial large enough to begin to
Neer et al. (50) demonstrated a significant reduction in both evaluate the wrist fracture incidence during teriparatide
vertebral and nonvertebral fractures, at doses of 20 and 40 therapy. Compared with placebo, treated patients had about
␮g/d. At the 20-␮g dose chosen for the clinical market, the half the number of wrist fractures. The apparent decrement
risk of new radiographic vertebral fractures was reduced by in radial BMD may be a combination of several effects in-
65% compared with placebo over a median treatment period duced by PTH that occur simultaneously, including in-
of 19 months (Fig. 2). If the analysis of vertebral fractures was creased endocortical remodeling, increased remodeling
restricted to moderate or severe deformities (⬎26% reduction space within the cortical haversian systems, and an increase
in vertebral height), the risk reduction was 90%. Figure 3 in measured area due to periosteal bone apposition as dis-
shows the incidence of nonvertebral fractures during the cussed previously in Section IV.B. In general, total body cal-
study. When all nonvertebral fragility fractures were as- cium measurements increase (42, 49 –51). The increase is
sessed, women were 53% less likely to fracture (relative risk, small, in the order of 1–2%, although in the study reported
0.47; confidence interval, 0.25– 0.88). It is of interest that there by Lindsay et al. (42) in which teriparatide was given to
TABLE 2. Controlled trials of PTH therapy

Total Inclusion Fractures (%)b ⌬ BMD (%)c

Age enrolled Teriparatide Duration Primary
Ref. Designa Vertebral BMD Control Vertebral Nonvertebral L/S FN
(yr) (no. of (␮g/d) (months) outcome
groups) fractures (T-score)

Postmenopausal
women
Lindsay, 1997 RT 62 34 (2) either or both 25 Long-term 36 L/S BMD 6 vs. 29 N/A 13 vs. 0d 2.7 vs. 0e,f
(42) 1 ⬍2.5 estrogen
Hodsman et al. • PTH Therapy for Osteoporosis

Neer, 2001 (50) RCT 70 1637 (3) either 2 20 – 40 Placebo 21 Fractures 4 –5 vs. 14e 3 vs. 5d 10 –14 vs. 1e 2.6 –3.6 vs. ⫺1f
or ⬍2 ⬍⫺1.0
Body, 2002 (49) RT 66 146 (2) ⬍2.5 40 Alendronate 14 L/S BMD N/A 4 vs. 14d 14 vs. 6e 4.5 vs. 2.8e,g
Hodsman, 2003 RCT 65 217 (4) ⬍2.5 50 –100h Placebo 12 L/S BMD N/A N/A 3– 8 vs. 0e ⫺0.2– 0.5 vs. ⫺0.7g
(53)
Black, 2003 RT 70 238 (3) ⬍2.5 100h Alendronate 12 BMD N/A N/A 6.3 vs. 4.6 vs. 6.1 0.8 vs. 2.0 vs. 1.8g
(60)
Men
Kurland, 2000 RCT 50 23 (2) ⬍2.5 25 Placebo 18 L/S BMD N/A N/A 14 vs. 0e 2.9 vs. 0d,g
(48)
Orwoll, 2003 RCT 59 437 (3) ⬍2.0 20 – 40 Placebo 12 L/S BMD N/A N/A 6 –9 vs. 0.5e 1.5–2.9 vs. 0.3d,g
(51)
Finkelstein, RT 58 83 (3) ⬍2.0 40 Alendronate 30 L/S BMD N/A N/A 18.1 vs. 7.9e vs. 14.8e 9.7 vs. 3.2e vs. 6.2e,g,i
2003 (86)
GIOP
Lane, 1998 (78) RT 63 51 (2) ⬍2.5 25 Long-term 12 L/S BMD 0 vs. 6 8 vs. 11 11 vs. 1e 1.6 vs. 0.8g
estrogen
Premenopause
Finkelstein, RT 32 43 (2) 40 Nafarelin 12 L/S BMD N/A N/A 2.1 vs. ⫺4.9e 0 vs. ⫺4.5e,g
1998 (77)
a
RT, Control group received active therapy; RCT, control group received supplements of calcium and vitamin D.
b
Percentage of enrolled patients.
c
Percentage change over baseline. L/S, Lumbar spine; FN, femoral neck.
d
⬍0.05, Placebo or control vs. PTH.
e
ⱕ0.01, Placebo or control vs. PTH.
f
Total FN.
g
FN (region of interest).
h
Intact PTH (hPTH 1– 84); 100 ␮g intact PTH ⫽ 40 ␮g teriparatide.
i
PTH vs. alendronate vs. combination.
Endocrine Reviews, August 2005, 26(5):688 –703 693

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694 Endocrine Reviews, August 2005, 26(5):688 –703 Hodsman et al. • PTH Therapy for Osteoporosis

nately, of more than 1600 patients enrolled in the overall trial,

only 365 were assessed with the Osteoporosis Assessment
Questionnaire instrument, limiting the statistical power of
the analysis. However, in this same fracture prevention trial,

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the incidence of any back pain (reported as an adverse event),
was significantly less in the group receiving 20 ␮g/d than in
the placebo group (17% vs. 23%; P ⬍ 0.02) (83). Similarly,
patients treated with teriparatide, 40 ␮g/d, were reported to
have significantly less back pain than those receiving alen-
dronate in the small head-to-head trial (6% vs. 19%; P ⫽
0.012), but this study did not document vertebral fractures as
FIG. 2. Reduction in the risk of new morphometric vertebral frac-
tures in postmenopausal women with severe osteoporosis after teripa- an outcome (49).
ratide, 20 ␮g/d, over a median treatment period of 19 months, com- To a degree, the cost effectiveness of osteoporosis therapy
pared with placebo. [Derived from Ref. 50.] depends on the number of patients who need to be treated
to prevent a fracture. Table 3 compares the fracture data
postmenopausal women on long-term estrogen therapy, the between teriparatide and two widely used bisphosphonates,
increment in total body calcium was linear and almost 8% alendronate and risedronate. The data are taken from the
over 3 yr. randomized clinical trials in which postmenopausal women
Therapy with teriparatide has consistently improved lum- were enrolled on the basis of having at least one prevalent
bar spine and femoral neck BMD in men (48, 51) and in vertebral fracture; in the four studies cited, the mean age of
postmenopausal women with GIOP (78). Indeed, changes in the study cohorts ranged from 69 –71 yr, and treatment
BMD and incremental changes in biochemical markers of duration ranged from 21 months (teriparatide) to 3 yr (alen-
bone turnover mirror closely those seen in postmenopausal dronate and risedronate). Although there may be other fac-
osteoporosis. Finkelstein et al. (77) have evaluated the effect tors influencing future fracture risk, the four study popula-
of teriparatide in younger women with acute estrogen de- tions should be quite comparable. In the absence of head-
ficiency after nafarelin therapy. In this study, BMD was to-head studies, this is a pragmatic way to compare
maintained during the 12-month treatment period, whereas effectiveness, because age and the prevalence of fractures,
women treated with nafarelin alone experienced sharp dec- before initiating osteoporosis therapy, greatly influence the
rements in both lumbar spine and femoral neck BMD mea- number who need to be treated calculation (84). As can be
surements (Table 2). These women received a relatively high seen, the apparent relative effectiveness of teriparatide and
dose of PTH (40 ␮g/d), but the specific activity of the peptide bisphosphonates is quite similar when used in postmeno-
was not mentioned. There is no obvious explanation as to pausal women at higher risk for fragility fractures. The Na-
why the bone densitometric changes were so much lower tional Institute for Clinical Excellence in the United Kingdom
than in the other trials utilizing teriparatide. has compared the cost-utility ratio between the bisphospho-
4. Health outcomes and cost effectiveness. Only one study has nates, raloxifene and teriparatide, using a modified individ-
evaluated health-related quality of life (82). Using a disease- ual Markov approach (85). The baseline model examines the
specific instrument, the Osteoporosis Assessment Question- cost-utility ratio of bisphosphonates, raloxifene and teripa-
naire (OPAQ), Oglesby et al. (106) reported on outcomes from ratide, in postmenopausal women with at least one prevalent
the teriparatide phase III randomized controlled trial. Al- vertebral fracture and a T score of less than ⫺2.5., stratified
though it could be clearly shown that incident vertebral and by ages 50 – 80 yr. At age 60, the cost-utility ratio (calculated
nonvertebral fractures were associated with a deteriorating in pounds per Quality of Life Year to prevent one clinical
quality of life (compared with those patients who did not fracture) of teriparatide is nearly 3-fold that of bisphospho-
fracture), there was no significant difference between the nates. It approximates that of the bisphosphonates, alendro-
teriparatide-treated patients and those on placebo. Unfortu- nate and risedronate, only when the modeled risk is 4-fold
higher than that of the baseline model. This increased level
of risk would represent women with either 1) two or more
fractures, a T score less than ⫺3.0 plus an additional major
but nonmodifiable risk factor; or 2) an “extremely” low T
score of less than – 4.0 (85). The National Institute for Clinical
Excellence analysis has the advantage that generally agreed
upon quantifiable risks and benefits were applied within a
single health care system; the much higher cost-utility ratio
for teriparatide as compared with the bisphosphonates is
driven by the cost of teriparatide rather than its efficacy.

FIG. 3. Cumulative incidence of new nonvertebral fractures, occur-

ring with minimal trauma, in postmenopausal women after teripa- B. Trials with intact PTH
ratide therapy, 20 ␮g/d, over a median treatment period of 19 months:
relative risk, 0.47 (confidence interval, 0.22– 0.88) compared with Intact PTH is undergoing phase III clinical trials. However,
placebo (Eli Lilly, Canada, Forteo Product Mongraph). [Derived from in the phase II studies with intact PTH, three doses (50, 75,
Ref. 50.] and 100 ␮g/d) were evaluated over 12 months (Table 2) (53).
Hodsman et al. • PTH Therapy for Osteoporosis Endocrine Reviews, August 2005, 26(5):688 –703 695

TABLE 3. Comparison of fracture risk reduction between teriparatide (for 19 months) and bisphosphonates (for 36 months) during the
clinical trials in postmenopausal women with at least one baseline incident vertebral fracture

Teriparatide Alendronate Risedronate Risedronate

Neer et al. (50) Black et al. (11) Harris et al. (13) Reginster et al. (14)

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New vertebral fractures
Relative risk (95% CI) 0.4 (0.2– 0.6) 0.5 (0.4 – 0.7) 0.6 (0.4 – 0.8) 0.5 (0.4 – 0.7)
Placebo incidence rate (%) 14 15 16 29
Absolute risk reduction (%) 9 7 5 11
NNT 11 9 20 10
New nonvertebral fractures
Relative risk (95% CI) 0.5 (0.3– 0.9) 0.8 (0.6 –1.0) 0.6 (0.4 – 0.9) 0.7 (0.4 –1.0)
Placebo incidence rate (%) 6 15 8 51
Absolute risk reduction (%) 3 3 3 15
NNT 34 34 43 20

Changes in BMD were dose dependent. At 100 ␮g/d, the increase to approximately 170 pg/ml within 30 min (an in-
dose currently under evaluation in phase III, the increments crement of 10-fold over baseline levels, which predominantly
in BMD were 7.8% at the lumbar spine, and 0.5% at the reflects measurement by the assay of endogenous intact
femoral neck after 12 months. There was a nonsignificant PTH), rapidly decline with a t1/2 of about 1 h, and return to
decrement of 1.5% in whole-body BMC. It is possible that the baseline by 4 h. Between 4 and 6 h, the serum calcium peaks,
small changes in femoral neck and whole-body bone mineral but the level remains within the normal physiological range,
measurements reflected transient imbalance between cortical with the increment being about 0.2 mmol/liter (0.8 mg/dl).
remodeling and bone formation. A subset of these phase II The increased serum calcium is sustained during the day but
study patients received sequential therapy with alendronate returns to baseline before the next dose. However, within the
for an additional 12 months and demonstrated very signif- pivotal study in postmenopausal women (50) postdose se-
icant increments at both measurement sites (52). As with rum calcium was above the upper limit of normal at least
teriparatide, intact PTH produced similar increments in bio- once in 11% of patients on teriparatide, 20 ␮g/d. Repeated
chemical markers of bone turnover (53). As yet, there are no serum calcium levels were assessed according to an algo-
data on the antifracture efficacy of intact PTH. Several other rithm, and only if persistently elevated were calcium sup-
PTH analogs have been evaluated in animal models of os- plements decreased or discontinued. Ultimately, the dose of
teoporosis, but there are no comparable studies in human teriparatide was reduced by 50% in only 3% of patients, and
subjects. persistent increments in serum calcium led to withdrawal of
active therapy in only one of 541 patients. Similar transient
rises in serum calcium have been reported during other
VI. Side Effects and Precautions controlled trials with teriparatide (51, 86). There is less in-
Only the study by Neer et al. (50) was large enough to formation for the chosen dose of intact PTH, 100 ␮g/d, but
consistently search for adverse events in teriparatide-treated the incidence of transient hypercalcemia may be higher (53,
patients vs. placebo. Circulating antibodies to teriparatide 60), and 8 –10% of patients may develop mild hypercalciuria
developed in 3% of the women receiving 20 ␮g/d, but these (60). After teriparatide treatment, there was a small increase
antibodies had no discernable effects on any of the measured in 24-h urinary calcium excretion by a median of 0.75 mmol
clinical outcomes. Antibody formation was not found after (30 mg)/d (50). However, the clinical trials with teriparatide
intact PTH therapy (53). During the teriparatide trial, the excluded patients with hypercalciuria or a history of renal
frequencies of headaches (8%) and nausea (8%) were no calculi within 5 yr, and the development of hypercalciuria
greater than in the placebo group. Nine percent reported required reduction in daily calcium supplements. Whereas
dizziness and 3% reported leg cramps. These two symptoms no clinical adverse events were associated with any incre-
were reported by significantly fewer (6% and 1%) of the ments in serum or urine calcium, the most efficient means of
control patients. They tend to occur within a few hours of identifying the small percentage of patients who require dose
injection. The incidence of side effects has been variable from reduction has yet to be determined.
study to study. Although there is not enough published
information to comment on side effects associated with intact
PTH, they are probably similar. A significant increase in
serum uric acid has been found in about 3% of patients after
teriparatide therapy (50) and also in patients treated with
intact PTH (60), several of whom developed acute gout.

A. Hypercalcemia and hypercalciuria

PTH injections consistently increased serum calcium. Fig-
ure 4 shows the pharmacokinetic profile of serum PTH and FIG. 4. Pharmacokinetic profile of teriparatide given by sc injection,
calcium observed during the phase III teriparatide fracture together with resulting changes in serum calcium (data on file, Eli
prevention trial. After injection, serum teriparatide levels Lilly, USA, www.fda.gov/ohrms/dockets/ac/01/slides/3761s2_01_lilly).
696 Endocrine Reviews, August 2005, 26(5):688 –703 Hodsman et al. • PTH Therapy for Osteoporosis

B. Osteosarcoma induction during PTH therapy. The use of PTH in patients

with a recent history of cancer has not been explored because
All three of the major teriparatide trials (in postmeno-
clinical trials routinely exclude such patients. In the phase III
pausal women with severe osteoporosis, in men with osteo-
teriparatide trial, nonosseous cancers developed in 40
porosis, and the first head-to-head trial against alendronate)

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women, with a higher incidence in the placebo group (4%)
(49 –51) were terminated prematurely because of the findings
than in the 20-␮g/d (2%) and 40-␮g/d (2%) groups, and this
of induced osteosarcoma in an ongoing carcinogenicity
apparent difference in cancer incidence was significant in the
study in rats. In this study, Fischer 344 rats were given PTH
20-␮g treatment group (P ⫽ 0.02) (50). There is therefore little
from infancy through senescence (from 8 wk of age through
current evidence to warrant concern that PTH therapy is
2 yr) (87). The administered doses would correspond to ap-
attached to a significant risk of inducing either bone or non-
proximately 30 – 4500 ␮g/d when given to a 60-kg human
osseous cancer, but it may be prudent not to recommend it
subject. Osteosarcoma was found at all dose levels, and, in
in patients with a history of cancer within the past 5 yr.
the lower dose ranges, was first detected after approximately
PTH should be avoided in patients with a history of neph-
20 months of therapy (87). It should be pointed out that
rolithiasis and/or gout, unless careful monitoring of serum
therapy with teriparatide at these doses causes gross abnor-
and urine calcium or uric acid is maintained. Before PTH
malities in bone tissue in the rat model, with overgrowth of
therapy is initiated, nutritional vitamin D status should be
trabecular bone to the point that the marrow space in both
evaluated with serum 25-OH vitamin D levels. Vitamin D
the metaphysis and diaphysis is almost completely replaced
deficiency (serum levels ⬍ 40 nmol/liter) (90) and insuffi-
by bone tissue (88). Osteosarcoma has also been reported in
ciency (⬍ 80 nmol/liter) (91) are relatively common. This is
a similar carcinogenicity study with intact PTH. Although
particularly relevant for patients with very low T scores, of
there was no difference in the low dose (10 ␮g/kg䡠d) com-
less than ⫺3.5, in whom nutritional osteomalacia should be
pared with controls, there was a dose-related incidence of
clearly excluded before PTH therapy is begun. Obviously,
osteosarcoma in the mid- (50 ␮g), and high- (100 ␮g) dose
PTH should not be considered if other metabolic bone dis-
groups over 2 yr. At the time of writing these results are
ease, including primary hyperparathyroidism or renal os-
available only in preliminary form (www.npsp.com/news/
teodystrophy, is suspected, although a theoretical case might
releasetxt.php?ReqId⫽471943).
be made for treating “osteoporotic” fractures in dialysis pa-
There is no substantive evidence of clinical osteosarcoma
tients with adynamic bone disease and severe functional
induction in clinical states of high, very prolonged PTH
hypoparathyroidism.
secretion (e.g., renal osteodystrophy). To date there have
been four case reports of coincident osteosarcoma in patients
with primary hyperparathyroidism, but the cause-and-effect
VII. PTH in Clinical Practice
relationship remains unproven (89). In the study of Neer et
al. (50), no osteosarcomas were found, but the rarity of these A. Candidates for PTH therapy
cancers in humans makes assessment of the relative risk
impossible at present. The relevance of the animal carcino- To date, almost all clinical trials of PTH have been carried
genicity findings to treating older subjects with severe os- out in postmenopausal women with osteoporosis, using
teoporosis may be minimal. In adult humans, in whom such teriparatide. Therefore our recommendations apply mainly
exaggerated pharmacological effects in bone do not occur, it to postmenopausal women, although men with osteoporosis
is unlikely that the risk of osteosarcoma would be increased should also be considered. The following three groups of
by daily treatment with PTH for a relatively small fraction of patients should be considered candidates for therapy with
the normal life span. An independent outside oncology ad- teriparatide. At present there are insufficient data to com-
visory board concluded that the rat carcinogenicity finding ment on intact PTH, which has yet to receive regulatory
is very unlikely to have relevance to humans treated with approval.
teriparatide. The approved labeling for teriparatide in the
1. Patients with preexisting osteoporotic fractures. The best ev-
United States limits its use to no more than 2 yr (88).
idence to date supporting the therapeutic efficacy of teripa-
ratide to reduce the risk of both vertebral and nonvertebral
C. Additional precautions fractures comes from the study by Neer et al. (50), which
tested teriparatide in postmenopausal women, over 65 yr of
In view of the carcinogenicity studies in animals, certain age, who also had prevalent vertebral fractures before ther-
warnings have been issued to avoid the use of teriparatide apy. However, in this trial, the risk for developing new
and, presumably, other PTH peptides in patients who might vertebral fractures was largely independent of initial lumbar
be at increased risk for osteosarcoma, i.e., patients with spine BMD and was seen in patients with T scores between
Paget’s disease, prior skeletal irradiation, unexplained in- –2.1 and –3.3 (79). Moreover, in this study, the risk for new
creases in serum bone-specific alkaline phosphatase, and vertebral fractures was reduced similarly, irrespective of the
adolescents in whom the epiphyses have not yet closed. In number of prevalent fractures before the onset of therapy.
addition to bone and kidney, many normal tissues express These data are in contrast to the antifracture efficacy of
the PTH/PTHrP receptor, including those of epithelial and bisphosphonates, where the fracture risk reduction is clearly
endothelial origin, and the receptor has been found in some dependent on the number of prevalent fractures as well as
solid tumors, including breast and clear-cell renal cancer. the reduction in BMD present before therapy is started (17,
This raises the theoretical possibility of nonosseous cancer 79, 92). Thus, PTH therapy is likely to be most effective in
Hodsman et al. • PTH Therapy for Osteoporosis Endocrine Reviews, August 2005, 26(5):688 –703 697

patients with preexisting “fragility” fractures irrespective of the manufacturer recommends that teriparatide not be used
whether measured BMD falls below the cut-off point defi- in situations where the risk of developing osteosarcoma
nition of osteoporosis (i.e., a T score of ⱕ⫺2.5). Because the might be increased, particularly in adolescents with open
increment in BMD in response to teriparatide is very similar epiphyses (in whom the incidence of osteosarcoma is much

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for men to that seen in women (51), the antifracture efficacy higher than in older individuals) and in older patients with
of PTH will likely be similar for men and women. Paget’s disease or previously treated with external ionizing
radiation.
2. Patients with very low bone density. The rapidity with which
increments in BMD are seen in response to teriparatide may B. Monitoring
make this a preferred therapy in individuals at particularly
high risk for incident fractures. Because fracture risk in- The clinical trials with teriparatide and intact PTH have
creases exponentially, doubling with each integer decrease in included algorithms for dose adjustment in response to hy-
BMD T score, such high-risk individuals may be arbitrarily percalcemia. However, the recent Food and Drug Adminis-
defined with T scores of –3.5 or below even in the absence of tration approval of teriparatide does not include recommen-
fractures. In the absence of a head-to-head comparative trial dations for monitoring serum calcium because persistent
comparing antifracture efficacy, whether teriparatide or hypercalcemia requiring dose reduction was uncommon
bisphosphonate therapy should be the preferred initial ther- (⬃3% of patients taking 20 ␮g/d), and the hypercalcemia that
apeutic choice in patients meeting the World Health Orga- was occasionally seen was mild. Although nausea and vom-
nizations’ definition of “severe osteoporosis” (a T score of iting were reported as significant, but occasional, adverse
–2.5 plus vertebral fractures) cannot be defined. In a short reactions to teriparatide, there was no correlation between
trial comparing teriparatide with alendronate, the incre- these symptoms and the rare incidence of hypercalcemia
ments in BMD at both the lumbar spine and femoral neck (data on file, Eli Lilly, Indianapolis, IN). Nonetheless, many
were significantly earlier and of greater magnitude for physicians may feel it prudent to monitor fasting predose
teriparatide (49). On the other hand, there is no evidence that serum calcium after 1 month of stable daily teriparatide
teriparatide is superior to bisphosphonates in its antifracture injections. If persisting hypercalcemia is found, decreasing
efficacy (Table 3), and therefore its much higher cost may not calcium supplements to ensure a total daily calcium intake
justify its use as a first-line therapy. of no more than 1000 mg would be the first action. If hy-
percalcemia persists, the frequency of injections can be re-
3. Patients with an unsatisfactory response to antiresorptive ther- duced to alternate days. Significant hypercalciuria, renal cal-
apy. There may be reasons to select teriparatide in patients culus formation, or nephrocalcinosis has not surfaced as a
previously treated with a potent antiresorptive agent, rec- clinical problem in patients receiving teriparatide.
ognizing that bisphosphonates may blunt or delay the ana- Consistent increments in serum uric acid have been re-
bolic response to PTH. Intolerance to the local upper gas- ported with teriparatide and intact PTH, but the utility of
trointestinal irritation by bisphosphonates would be a clear monitoring serum uric acid in the absence of a history of gout
indication. An incident fragility fracture during bisphospho- is unclear.
nate treatment is not an indication of treatment failure of The frequency of BMD measurement should not be any
itself: no treatment reduces the risk of fracture to zero. How- different from other osteoporosis therapies; the small but
ever, an incident fracture in the face of continuing and sig- expected decrease in peripheral cortical measurement sites
nificant reduction in BMD despite 2 yr of apparently com- (e.g., the distal radius) occurs during the first year of treat-
pliant therapy would be evidence of an unsatisfactory ment (as discussed above), but is not associated with an
response to the bisphosphonate. In such cases it would increased risk for wrist fracture (50). Increments in biochem-
be important to exclude secondary causes of osteoporosis, ical markers of bone turnover are consistently seen beginning
including vitamin D deficiency, other endocrine conditions, within the first 1–3 months of teriparatide and intact PTH
or unrecognized intestinal malabsorption syndromes. At treatment, but there is no indication that these measurements
present there is no evidence that patients with an unsatis- provide any guidance to therapeutic decisions.
factory response to bisphosphonates will have a more fa-
vorable outcome to PTH, particularly if future studies con- C. Duration of therapy
firm that some or all bisphosphonates blunt the anabolic
action of PTH (see below). At present, teriparatide therapy is approved for 2-yr du-
ration. This is largely because longer term data are not avail-
4. Patients who should not be treated. Most studies with either able from randomized, placebo-controlled studies. Further-
teriparatide or intact PTH have involved postmenopausal more, the prevalence of osteosarcoma in rats was dependent
women or men over the age of 50. There is no clinical reason on dose and duration of treatment (87).
for an age restriction, but younger men and women with a
low BMD as their sole abnormality should probably not be D. PTH and cotherapy with antiresorptive agents
treated, as prevalent fragility fractures are unusual in indi-
viduals under the age of 50, and the clinical significance of The development of PTH as a therapy for osteoporosis
low T scores in this age group is unclear. Safety in pregnancy raises many questions concerning how it should be used in
has not been determined, and PTH should not be prescribed concert with other treatments. The pivotal studies that dem-
to women in their reproductive years. Although the risk of onstrated the effectiveness of PTH in increasing BMD and
osteosarcoma is not considered to be significant for humans, reducing fracture risk were conducted as placebo-controlled
698 Endocrine Reviews, August 2005, 26(5):688 –703 Hodsman et al. • PTH Therapy for Osteoporosis

trials involving participants not receiving other treatments On the other hand, there are two randomized controlled
immediately before or during PTH treatment. Hence, there studies (Table 2) that show that alendronate (either started
are few data that directly inform a variety of clinical situa- shortly before or concurrently) significantly modifies the ex-
tions that routinely arise when treatment recommendations pected outcomes of PTH therapy over 1–2.5 yr (60, 86). Both

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for patients with osteoporosis are being formulated. Key studies, one in postmenopausal women treated with intact
questions that must be addressed by targeted research in- PTH, 100 ␮g/d (60), and one in men treated with teriparatide,
clude whether PTH therapy can be effectively used in pa- 40 ␮g/d (86), showed that the hypothesized synergy be-
tients who are already being treated with antiresorptive tween the two drugs did not occur. If anything, the anabolic
drugs, whether PTH should be administered in combination effect of PTH appeared to be blunted, particularly the in-
with other treatments, and what therapeutic approach crements in biochemical markers of bone metabolism. There
should be adopted at the conclusion of treatment with PTH. was no additive effect on BMD gains for a combination of
This final question is particularly pertinent for a treatment intact PTH and alendronate, whereas this bisphosphonate
that, for various reasons, is likely to be seen as a short-term actually reduced the BMD gains observed with teriparatide
approach to produce a rapid and significant improvement in alone. As expected, patients treated with alendronate alone
bone mass. Moreover, the drug is currently given by daily showed smaller increments than either teriparatide alone or
injection and is considerably more expensive than antire- the combination. Somewhat in support of these observations,
sorptive therapy, and there remain some concerns about Ettinger et al. (100) found that when teriparatide, 20 ␮g/d,
long-term safety. was substituted for alendronate therapy (previously given
for at least 1 yr to postmenopausal women with osteoporo-
1. The influence of previous or concomitant antiresorptive therapy. sis), the expected increments in biochemical markers of bone
Although the anabolic effects of PTH might be accentuated if formation and BMD were delayed for 6 months; in this study,
osteoclastic bone resorption is suppressed, there is also concern subsequent changes in these outcomes appeared to improve
that the decrease in overall remodeling rates induced by anti- as expected. No clinical information currently exists regard-
resorptive agents might impair the ability of PTH to stimulate ing interactions between other bisphosphonates and PTH.
Given that many patients with severe osteoporosis may al-
osteoblastic activity and new bone formation. Some (93, 94), but
ready be receiving antiresorptive therapy, this issue has im-
not all (95, 96), studies in animals suggest that pretreatment
portant implications for planning optimal therapy with PTH,
with calcitonin, clodronate, risedronate, or estrogen does not
particularly if potent bisphosphonates prevent or delay the
materially blunt the bone-forming effects of PTH.
anabolic response.
a. Estrogen and raloxifene. Trials in postmenopausal women
who had been on previous long-term estrogen replacement, 2. Antiresorptive therapy after PTH. After cessation of teripa-
and continued during teriparatide therapy, revealed that the ratide therapy, BMD tends to fall (103). Although some an-
expected response to PTH occurred nonetheless, as reflected tifracture efficacy of PTH has been shown to persist for some
by increases in markers of bone remodeling and bone density time after the cessation of therapy (103), it may be desirable
(42, 97, 98). When teriparatide was added to established to retain the new bone formed during the treatment period.
estrogen therapy, the observed increments in spinal BMD Some animal studies suggest that estrogen treatment can
(⬃13%) and in the hip (2.7– 4.4%) over 3 yr were certainly sustain higher levels of bone mass after PTH therapy is
consistent with those found in the randomized controlled discontinued. However, in the study of Roe et al. (104) in
trials (42, 97). Similarly, postmenopausal women receiving which a 29% improvement in spine BMD, measured by DXA,
both estrogen and glucocorticoids responded well to PTH was seen after 2 yr of treatment with PTH and estrogen,
treatment (78). Ettinger et al. (100) reported similar findings continuing estrogen after the PTH was stopped did not to-
in postmenopausal women who had been treated for at least tally prevent bone loss, and a 4% decline in lumbar BMD was
12 months with raloxifene before teriparatide was substi- seen in the subsequent year. These trends have been ob-
tuted, namely that increments in biochemical markers of served in other studies (97, 105). Two studies have explored
bone formation and BMD were similar to those expected the benefit of alendronate after PTH is stopped. In one study
from historical controls, suggesting that raloxifene does not in postmenopausal osteoporotic women, Rittmaster et al. (52)
blunt the anabolic effects of PTH. found that alendronate given sequentially for 1 yr after intact
PTH therapy led to an overall increase of 14.6% at the spine
b. Bisphosphonates. There is increasing evidence from some together with significant increments in the femoral neck and
(86, 100), but not all (101, 102), studies that prior therapy with total body calcium. The typical improvement normally seen
the potent bisphosphonate, alendronate, may indeed blunt the with alendronate was added to the prior improvement pro-
effectiveness of PTH by mitigating the expected increments in duced by intact PTH. Bone turnover declined but still re-
both bone turnover and bone density. On the one hand, Cos- mained above that of the original placebo (no PTH) group
man et al. (101, 102) have consistently reported in preliminary (52). In a study of the effect of alendronate for 2 yr after PTH
findings that women with postmenopausal osteoporosis, who treatment in osteoporotic men, the findings were similar;
had been previously treated with alendronate for well over 1 yr, those on no antiresorptive therapy after stopping PTH even-
responded with the expected changes in BMD and biochemical tually began to lose bone (99). A different approach has been
markers of bone turnover when treated with teriparatide. How- the use of intermittent PTH used cyclically with an antire-
ever, their findings were compared with historical controls and sorptive. Calcitonin has been studied in this manner, but the
were not internally controlled. combined cyclical therapy was not found to be superior to
Hodsman et al. • PTH Therapy for Osteoporosis Endocrine Reviews, August 2005, 26(5):688 –703 699

cyclical PTH alone (76). The final answer to the best combi- pausal women with GIOP and who were also receiving long-
nation or sequence of PTH and an antiresorptive medication term estrogen therapy (grade B). There is no evidence that
awaits larger trials and, particularly, fracture data. concurrent estrogen therapy is required for the anabolic ac-
tion of teriparatide (grade D). Teriparatide should also be

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effective in men with GIOP (grade D), but there are no
antifracture efficacy data for men or women with GIOP.
VIII. Summary
4. Teriparatide may be considered for the management of
Teriparatide [hPTH(1–34)] is the first agent in a unique individuals at particularly high risk for fractures, including
class of anabolic therapies acting on the skeleton. Current subjects who are younger than age 65 yr and who have
evidence supports the concept that teriparatide significantly particularly low BMD measurements (T scores ⬍ 3.5) (grade
reduces fracture risk (Table 2), by improving bone microar- D). There is as yet no head-to-head trial, comparing the
chitecture as well as enhancing overall bone mass. The intact antifracture efficacy of PTH with antiresorptive agents. This
hormone hPTH(1– 84) may have similar potential, pending recommendation is based on the biologically plausible mech-
completion of ongoing phase III trials of fracture efficacy. anism that PTH produces a rapid improvement in skeletal
PTH should be considered as an alternative therapy to ex- architecture, whereas antiresorptive agents do not. Thus,
isting antiresorptive agents for the prevention of fractures in patients at very high risk of fracture may benefit in the long
patients with severe osteoporosis. Teriparatide appears to be term from initiating treatment with PTH. The gradient of risk
superior to antiresorptive therapy (alendronate) in improv- may be even higher in the face of other major risk factors such
ing BMD at the lumbar spine. However, there are as yet no as low body mass index, glucocorticoid use, or gastrointes-
direct comparisons of the antifracture efficacy between these tinal disease leading to malabsorption.
two classes of agents. A historical comparison of antifracture 5. Therapy with alendronate should be discontinued when
efficacy between teriparatide, on the one hand, and two treatment with teriparatide is initiated (grade A) (60, 86).
bisphosphonates (alendronate and risedronate), on the other, Controlled clinical trials suggest that alendronate may blunt
does not suggest superior antifracture efficacy for teripa- the expected anabolic effects, if started before, or concur-
ratide (Table 3). rently, with PTH. At present there is no indication that the
There is now evidence that prior therapy with a potent interactions between alendronate and PTH are specific to this
bisphosphonate (alendronate) may blunt the anabolic action
drug or represent a class effect that will be seen with other
of teriparatide, although the mechanism for this is not
bisphosphonates. There is no evidence for any clinical ad-
known. The same is not true for postmenopausal women
vantages to adding an antiresorptive agent to PTH, and no
chronically treated with estrogen or raloxifene. Nonetheless,
studies have approached such an interaction with respect to
there is no evidence to support a need for concurrent therapy
fracture rates. To date there is no evidence that continuing
with an antiresorptive agent during treatment with PTH,
either estrogen or raloxifene during PTH therapy confers
other than providing appropriate supplemental calcium and
vitamin D to ensure adequate availability of calcium to min- either clinical advantage or disadvantage.
eralize newly formed bone matrix. 6. Therapy with an antiresorptive agent after cessation of
teriparatide is recommended to further enhance increments
in BMD measurements (grade C) (52). There is as yet no
evidence that this approach will further reduce fracture risk
IX. Recommendations (grade D).
7. Therapy with teriparatide is not recommended beyond
1. Teriparatide should be considered as a treatment for
2 yr (grade D). In part this recommendation is based on the
postmenopausal women with severe osteoporosis (grade A)
current limitations of the experience with this agent and the
(50). The World Health Organization’s definition of severe
osteoporosis includes a prevalent fragility fracture in the lack of longer term data. Moreover, the induction of osteo-
presence of a T score less than ⫺2.5. However, the evidence sarcoma in the rat model was dependent on both dose and
to date supports a clinically significant reduction in fracture duration of therapy.
risk in postmenopausal women with prevalent fractures that 8. Total daily calcium intake from both supplement and
is independent of BMD. This benefit was seen with T scores dietary sources should be limited to 1500 mg, together with
as high as –2 (79). adequate vitamin D intake (ⱕ1000 U/d) (grade D).
2. Teriparatide should be considered for men with severe 9. Routine serum calcium monitoring may not be required
osteoporosis (grade B) (48, 51). Teriparatide results in incre- for safety monitoring (grade D). However, after the first
ments in BMD (as measured by DXA) when given to men month of therapy, it may be prudent to measure the “trough”
with osteoporosis over relatively short periods of up to 18 serum calcium, just before the daily teriparatide injection. In
months. These increments are similar to those observed in the small percentage of individuals with increased serum
postmenopausal women with severe osteoporosis. However, calcium during PTH therapy, adjustment of dietary calcium
there are no data for the efficacy of teriparatide therapy to supplements or reduced teriparatide dosing frequency will
reduce fractures in men. usually be sufficient.
3. Teriparatide should be considered for patients with 10. Routine measurements of biochemical markers of bone
established GIOP who require long-term steroid treatment turnover are not recommended to monitor the response to
(grade B) (78). Teriparatide increased BMD in postmeno- treatment over a 2-yr cycle with teriparatide (grade D).
700 Endocrine Reviews, August 2005, 26(5):688 –703 Hodsman et al. • PTH Therapy for Osteoporosis

Acknowledgments 15. Cranney A, Guyatt G, Griffith L, Wells G, Tugwell P, Rosen C

2002 Meta-analysis of therapies for postmenopausal osteoporosis.
We thank Elke Henneberg for her editorial support and assistance IX. Summary of meta-analyses of therapies for postmenopausal
with the preparation of this manuscript. osteoporosis. Endocr Rev 23:517–523
16. Black DM, Thompson ED, Bauer DC, Ensrud K, Musliner T,

Downloaded from https://academic.oup.com/edrv/article/26/5/688/2355192 by Carol Davila University of Medicine and Pharmacy Bucharest user on 17 July 2024
Address all correspondence and requests for reprints to: Anthony B. Hochberg MC, Nevitt MC, Suryawanshi S, Cummings SR; Frac-
Hodsman, Professor of Medicine, University of Western Ontario, 噦 St. ture Intervention Trial 2000 Fracture risk reduction with alendro-
Joseph’s Health Care, Room 2F-15, 268, Grosvenor Street, London, On- nate in women with osteoporosis: the Fracture Intervention Trial.
tario N6A 4V2, Canada. E-mail: anthony.hodsman@sjhc.london.on.ca FIT Research Group. J Clin Endocrinol Metab 85:4118 – 4124
17. McClung MR, Geusens P, Miller PD, Zippel H, Bensen WG, Roux
C, Adami S, Fogelman I, Diamond T, Eastell R, Meunier PJ,
Reginster JY; Hip Intervention Program Study Group 2001 Effect
of risedronate on hip fracture risk in elderly women. N Engl J Med
References 344:333–340
18. Ringe JD, Orwoll E, Daifotis A, Lombardi A 2002 Treatment of
1. Meltzer S, Leiter L, Daneman D, Gerstein HC, Lau D, Ludwig S, male osteoporosis: recent advances with alendronate. Osteoporos
Yale JF, Zinman B, Lillie D 1998 Clinical practice guidelines for the Int 13:95–199
management of diabetes in Canada. Canadian Diabetes Associa- 19. Adachi JD, Roux C, Pitt PI, Cooper C, Moniz C, Dequeker J,
tion. Can Med Assoc J 159(Suppl 8):S1–S29 Ioannidis G, Cawley MI, Jenkins EA, Walker-Bone KE, Pack S,
2. Rosen CJ, Bilezikian JP 2001 Anabolic therapy for osteoporosis. Stephenson GF, Laan RF, Brown J, Geusens P 2000 A pooled data
J Clin Endocrinol Metab 86:957–964 analysis on the use of intermittent cyclical etidronate therapy for
3. Watson PH, Hanley DA 1993 Parathyroid hormone: regulation of the prevention and treatment of corticosteroid induced bone loss.
synthesis and secretion. Clin Invest Med 16:58 –77 J Rheumatol 27:2424 –2431
4. Segre GV, D’Amour P, Potts JT 1976 Metabolism of radioiodinated 20. Adachi JD, Saag KG, Delmas PD, Lierman UA, Emkey RD, See-
bovine parathyroid hormone in the rat. Endocrinology 99:1645–1652 man E, Lane NE, Kaufman JM, Poubelle PE, Hawkins F, Correa-
5. Divieti P, Inomata N, Singh R, Juppner H, Bringhurst FR 2001 Rotter R, Menkes CJ, Rodriguez-Portales JA, Schnitzer TJ, Block
Receptors for the carboxyl-terminal region of PTH (1– 84) are highly JA, Wing J, McIlwain HH, Westhovens R, Brown J, Melo-Gomes
expressed in osteocytic cells. Endocrinology 142:916 –925 JA, Gruber BL, Yanover MJ, Leite MO, Siminoski KG, Nevitt MC,
6. Sutherland MK, Rao LG, Wylie JN, Gupta A, Ly H, Sodek J, Sharp JT, Malice MP, Dumortier T, Czachur M, Carofano W,
Murray TM 1994 Carboxyl-terminal parathyroid hormone peptide Daifotis A 2001 Two year effects of alendronate on bone mineral
(53– 84) elevates alkaline phosphatase and osteocalcin mRNA lev- density and vertebral fracture in patients receiving glucocorticoids:
els in SaOS-2 cells. J Bone Miner Res 9:453– 458 a randomized, double-blind, placebo-controlled extension trial. Ar-
7. Reeve J, Meunier PJ, Parsons JA, Bernat M, Bijvoet OL, Courpron thritis Rheum 44:201–211
P, Edouard C, Klenerman L, Neer RM, Renier JC, Slovik D, 21. Wallach S, Cohen S, Reid DM, Hughes RA, Hosking DJ, Laan RF,
Vismans FJ, Potts Jr JT 1980 Anabolic effect of human parathyroid Doherty SM, Maricic M, Rosen C, Brown J, Barton I, Chines AA
hormone fragment on trabecular bone in involutional osteoporosis: 2000 Effects of risedronate treatment on bone density and vertebral
a multicentre trial. Br Med J 280:1340 –1344 fracture in patients on corticosteroid therapy. Calcif Tissue Int
8. Hodsman AB, Hanley DA, Watson PH, Fraher LJ 2002 Pharma- 67:277–285
cologic mechanisms of therapeutics: parathyroid hormone. In: 22. Watts NB, Adami S, Chesnut CH 2001 Risedronate reduces the risk
Bilezikian JB, Raisz LG, Rodan GA, eds. Principles of bone biology. of clinical vertebral fractures in just 6 months. J Bone Miner Res
San Diego: Academic Press; 1305–1324 16(Suppl 1):S407
9. Storm T, Thamsborg G, Steiniche T, Genant HK, Sorensen OH 23. Chavassieux PM, Arlot ME, Reda C, Wei L, Yates AJ, Meunier PJ
1990 Effect of intermittent cyclical etidronate therapy on bone mass 1997 Histomorphometric assessment of the long-term effects of
and fracture rate in women with postmenopausal osteoporosis. alendronate on bone quality and remodelling in patients with os-
N Engl J Med 322:1265–1271 teoporosis. J Clin Invest 100:1475–1480
10. Watts NB, Harris ST, Genant HK, Wasnich RD, Miller PD, Jack- 24. Dufresne TE, Chmielewski PA, Manhart MD, Johnson TD, Borah
son RD, Licata AA, Ross P, Woodson GC, Yanover MJ 1990 B 2003 Risedronate preserves bone architecture in early postmeno-
Intermittent cyclical etidronate treatment of postmenopausal os- pausal women in 1 year as measured by three-dimensional micro-
teoporosis. N Engl J Med 323:73–79 computed tomography. Calcif Tissue Int 73:423– 432
25. Boivin GY, Chavassieux PM, Santora AC, Yates J, Meunier PJ
11. Black DM, Cummings SR, Karpf DB, Cauley JA, Thompson DE,
2000 Alendronate increases bone strength by increasing the mean
Nevitt MC, Bauer DC, Genant HK, Haskell WL, Marcus R, Ott
degree of mineralization of bone tissue in osteoporotic women.
SM, Torner JC, Quandt SA, Reiss TF, Ensrud KE 1996 Random-
Bone 27:687– 694
ized trial of effect of alendronate on risk of fracture in women with
26. Seeman E 2003 Bone quality. Osteoporos Int 14:S3–S7
existing vertebral fractures. Lancet 348:1535–1541
27. Rossouw JE, Anderson GL, Prentice RL, LaCroiz AZ, Kooperberg C,
12. Cummings SR, Black DM, Thompson, DE, Applegate WB, Bar- Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC,
rett-Connor E, Musliner TA, Palermo L, Prineas R, Rubin SM, Kotchen JM, Ockene J; Writing Group for the Women’s Health
Scott JC, Bogt T, Wallace R, Yates AJ, LaCrois AZ 1998 Effect of Initiative Investigators 2002 Risks and benefits of estrogen plus pro-
alendronate on risk fracture in women with low bone density but gestin in healthy postmenopausal women. JAMA 288:321–333
without vertebral fractures. Results from the Fracture Intervention 28. Ettinger B, Black DM, Mitlak BH, Knickerbocker RK, Nickelsen
Trial. JAMA 280:2077–2082 T, Genant HK, Christiansen C, Delmas PD, Zanchetta JR, Stakke-
13. Harris ST, Watts NB, Genant HK, McKeever CD, Hangartner T, stad J, Gluer CC, Krueger K, Cohen FJ, Eckert S, Ensrud KE,
Keller M, Chesnut 3rd CH, Brown J, Eriksen EF, Hoseyni MS, Avioli LV, Lips P, Cummings SR 1999 Reduction of vertebral
Axelrod DW, Miller PD 1999 Effects of risedronate treatment on fracture risk in post menopausal women with osteoporosis treated
vertebral and nonvertebral fractures in women with postmeno- with raloxifene. Results from a 3-year randomized clinical trial.
pausal osteoporosis: a randomized controlled trial. Vertebral Effi- JAMA 282:637– 645
cacy with Risedronate Therapy (VERT) Study Group. JAMA 282: 29. Chesnut 3rd CH, Silverman S, Andriano K, Genant H, Gimona
1344 –1352 A, Harris S, Kiel D, LeBoff M, Maricic M, Miller P, Moniz C,
14. Reginster J, Minne HW, Sorensen OH, Hooper M, Roux C, Brandi Peacock M, Richardson P, Watts N, Baylink D 2000 A random-
ML, Lund B, Ethgen D, Pack S, Roumagnac I, Eastell R 2000 ized trial of nasal spray salmon calcitonin in postmenopausal
Randomized trial of the effects of risedronate on vertebral fractures women with established osteoporosis: the prevent recurrence
in women with established postmenopausal osteoporosis. Osteo- of osteoporotic fractures study. PROOF Study Group. Am J Med
poros Int 11:83–91 109:267–276
Hodsman et al. • PTH Therapy for Osteoporosis Endocrine Reviews, August 2005, 26(5):688 –703 701

30. Lips P 2001 Vitamin D deficiency and secondary hyperparathy- osteoporosis in men: effects on bone mineral density and bone
roidism in the elderly: consequences for bone loss and fractures and markers. J Clin Endocrinol Metab 85:3069 –3076
therapeutic implications. Endocr Rev 22:477–501 49. Body JJ, Gaich GA, Scheele WH, Kulkarni PM, Miller PD, Peretz
31. Chapuy MC, Arlot ME, Delmas PD, Meunier PJ 1994 Effect of A, Dore RK, Correa-Rotter R, Papaioannou A, Cumming DC,
calcium and cholecalciferol treatment for three years on hip frac- Hodsman AB 2002 A randomized double-blind trial to compare the

Downloaded from https://academic.oup.com/edrv/article/26/5/688/2355192 by Carol Davila University of Medicine and Pharmacy Bucharest user on 17 July 2024
tures in elderly women. Br Med J 308:1081–1082 efficacy of teriparatide [recombinant human parathyroid hormone
32. Dawson-Hughes B, Harris SS, Krall EA, Dallal GE 1997 Effect of (1–34)] with alendronate in postmenopausal women with osteo-
calcium and vitamin D supplementation on bone density in men porosis. J Clin Endocrinol Metab 87:4528 – 4535
and women 65 years of age or older. N Engl J Med 337:670 – 676 50. Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Re-
33. Recker RR, Davies KM, Dowd RM, Heaney RP 1999 The effect of ginster JY, Hodsman AB, Eriksen EF, Ish-Shalom S, Genant HK,
low-dose estrogen and progesterone therapy with calcium and Wang O, Mitlak BH 2001 Effect of parathyroid hormone (1–34) on
vitamin D on bone in elderly women. Ann Intern Med 130:897–904 fractures and bone mineral density in postmenopausal women
34. Trivedi DP, Doll R, Khaw KT 2003 Effect of four monthly oral with osteoporosis. N Engl J Med 344:1434 –1441
vitamin D3 (cholecalciferol) supplementation on fractures and 51. Orwoll ES, Scheele WH, Paul S, Adami S, Syversen U, Diez-Perez
mortality in men and women living in the community: a random- A, Kaufman JM, Clancy AD, Gaich GA 2003 The effect of teripa-
ised double-blind controlled trial. Br Med J 326:469 – 475 ratide [human parathyroid hormone (1–34)] therapy on bone den-
35. Parfitt AM 1991 Use of bisphosphonates in the prevention of bone sity in men with osteoporosis. J Bone Miner Res 18:9 –17
loss and fractures. Am J Med 91(Suppl 5B):S42–S46 52. Rittmaster RS, Bolognese M, Ettinger MP, Hanley DA, Hodsman
36. Roschger P, Rinnerthaler S, Yates J, Rodan GA, Fratzi P, Klaush- AB, Kendler DL, Rosen CJ 2000 Enhancement of bone mass in
ofer K 2003 Alendronate increases the degree and uniformity of osteoporotic women with parathyroid hormone followed by alen-
mineralization in cancellous bone and decreases the porosity in dronate. J Clin Endocrinol Metab 85:2129 –2134
cortical bone of osteoporotic women. Bone 29:185–191 53. Hodsman AB, Hanley DA, Ettinger MP, Bolognese MA, Fox J,
37. Hernandez C, Beaupre GS, Marcus R, Carter DR 2001 A theoret- Metcalfe AJ, Lindsay R 2003 Safety and efficacy of human para-
ical analysis of the contributions of remodelling space, mineral- thyroid hormone (1– 84) in increasing bone mineral density in post-
ization, and bone balance to changes in bone mineral density dur- menopausal osteoporosis. J Clin Endocrinol Metab 88:5212–5220
ing alendronate treatment. Bone 29:511–516 54. Mashiba T, Burr DB, Turner CH, Sato M, Cain RL, Hock JM 2001
38. Bradbeer JN, Arlot ME, Meunier PJ, Reeve J 1992 Treatment of Effects of human parathyroid hormone (1–34) LY333334, on bone
osteoporosis with parathyroid peptide (hPTH 1034) and oestro- mass, remodelling, and mechanical properties of cortical bone dur-
gen: increase in volumetric density of iliac cancellous bone may ing the first remodelling cycle in rabbits. Bone 28:538 –547
depend on reduced trabecular spacing as well as increased thick- 55. Burr DB, Hirano T, Turner CH, Hotchkiss C, Brommage R, Hock
ness of packets of newly formed bone. Clin Endocrinol (Oxf) JM 2001 Intermittently administered human parathyroid hormone
37:282–289 (1–34) treatment increases intracortical bone turnover and porosity
39. Hodsman AB, Kisiel M, Adachi JD, Fraher LJ, Watson PH 2000 without reducing bone strength in the humerus of ovariectomized
cynomolgus monkeys. J Bone Miner Res 16:157–165
Histomorphometric evidence for increased bone turnover and cor-
56. Hirano T, Burr DB, Cain RL, Hock JM 2000 Changes in geometry
tical thickness without increased cortical porosity after 2 years of
and cortical porosity in adult, ovary-intact rabbits after 5 months
cyclical hPTH (1–34) therapy in women with severe osteoporosis.
treatment with LY333334. Calcif Tissue Int 66:456 – 460
Bone 27:311–318
57. Hirano T, Burr DB, Turner CH, Sato M, Cain RL, Hock JM 1999
40. Dempster DW, Cosman F, Kurland ES, Zhou H, Nieves J,
Anabolic effects of human biosynthetic parathyroid hormone frag-
Woelfert L, Shane E, Plavetic K, Muller R, Bilezikian J, Lindsay
ment (1–34), LY333334, on remodelling and mechanical properties
R 2001 Effects of daily treatment with parathyroid hormone on
of cortical bone in rabbits. J Bone Miner Res 14:536 –545
bone microarchitecture and turnover in patients with osteoporosis: 58. Cann CE, Roe EB, Sanchez SD, Arnaud CD 1999 PTH effects in
a paired biopsy study. J Bone Miner Res 16:1846 –1853 the femur: envelope-specific responses by 3D-QCT in postmeno-
41. Hodsman AB, Steer BM 1993 Early histomorphometric changes in pausal women. J Bone Miner Res 14(Suppl 1):S137 (Abstract)
response to parathyroid hormone therapy in osteoporosis: evi- 59. Zanchetta JR, Bogado CE, Ferretti JL, Wang O, Wilson MG, Sato M,
dence for novo bone formation on quiescent cancellous surfaces. Gaich GA, Dalsky GP, Myers SL 2003 Effects of teriparatide [recom-
Bone 14:523–527 binant human parathyroid hormone (1–34)] on cortical bone in post-
42. Lindsay R, Nieves J, Formica C, Henneman E, Woelfert L, Shen menopausal women with osteoporosis. J. Bone Miner Res 18:539 –543
V, Dempster D, Cosman F 1997 Randomised controlled study of 60. Black DM, Greenspan SL, Ensrud KE, Palermo L, McGowan JA,
effect of parathyroid hormone on vertebral-bone mass and fracture Lang TF, Garnero P, Bouxsein ML, Bilezikian JP, Rosen CJ; PaTH
incidence among postmenopausal women on oestrogen with os- Study Investigators 2003 The effects of parathyroid hormone and
teoporosis. Lancet 350:550 –555 alendronate alone or in combination in postmenopausal osteopo-
43. Dempster DW, Zhou H, Cosman F 2001 PTH treatment directly rosis. N Engl J Med 349:1207–1215
stimulates bone formation in cancellous and cortical bone in hu- 61. Semanick LM, Uusi-Rasi K, Zanchetta JR, Bogardo CE, Eriksen
mans. J Bone Miner Res 16(Suppl 1):S179 (Abstract) EF, Sato M, Beck TJ 2003 Teriparatide [rhPTH (1–34)] treatment
44. Leaffer D, Sweeney M, Kellerman LA, Avnur Z, Krstenansky JL, improves the structure of the proximal femur in women with
Vickery BH, Caulfield JP 1995 Modulation of osteogenic cell ul- osteoporosis. J Bone Miner Res 18(Suppl 1):S40 (Abstract)
trastructure by RS-23581, an analog of human parathyroid hor- 62. Hyldstrup L, Jorgensen JT, Gaich G 2001 Assessment of effects of
mone (PTH)-related peptide-(1–34), and bovine PTH-(1–34). En- LY333334 [recombinant human parathyroid hormone (1–34)] on cor-
docrinology 136:3624 –3631 tical bone using digital x-ray radiogrammetry. Bone 28(Suppl 1):S97
45. Pagitt AM 2002 Parathyroid hormone and periosteal expansion. (Abstract)
J Bone Miner Res 17:1741–1743 63. Lindsay R, Cosman F, Nieves J, Woelfert L 2000 Does treatment
46. Jiang Y, Zhao JJ, Mitlak BH, Wang O, Genant HK, Ericson EF 2003 with parathyroid hormone increase vertebral size? Osteoporos Int
Recombinant human parathyroid hormone (1–34) [teriparatide] 11 (Suppl 2):S206 (Abstract)
improves both cortical and cancellous bone structure. J Bone Miner 64. Uusi-Rasi K, Beck TJ, Oreskovic TL, Sato M, Borgado CE,
Res 18:1932–1941 Zanchetta JR 2002 Teriparatide [rhPTH(34)] improves the struc-
47. Jerome CP, Burr DB, VanBibber T, Hock JM, Brommage R 2001 tural geometry of the hip. J Bone Miner Res 17(Suppl 1):S208 (Ab-
Treatment with human parathyroid hormone (1–34) for 18 months stract)
increases cancellous bone volume and improves trabecular archi- 65. Gam SM 1970 The earlier gain and later loss of cortical bone.
tecture in ovariectomized cynomolgus monkeys (Macaca fascicu- Springfield, IL: Charles C. Thomas
laris). Bone 28:150 –159 66. Duan Y, Seeman E, Turner CH 2001 the biomechanical basis of
48. Kurland ES, Cosman F, McMahon DJ, Rosen CJ, Lindsay R, vertebral body fragility in men and women. J Bone Miner Res
Bilezikian JP 2000 Parathyroid hormone as a therapy for idiopathic 16:2276 –2283
702 Endocrine Reviews, August 2005, 26(5):688 –703 Hodsman et al. • PTH Therapy for Osteoporosis

67. Duan Y, Turner CH, Kim BT, Seeman E 2001 Sexual dimorphism duce the risk of osteoporotic fractures? An evaluation of the evi-
in vertebral fragility is more the result of gender differences in dence to date. Can Med Assoc J 166:1426 –1430
age-related bone gain than bone loss. J Bone Miner Res 6:2267–2275 85. National Institute for Clinical Excellence, Final Appraisal 2004
68. Misof BM, Roschger P, Cosman F, Kurland ES, Tesch W, Mess- The clinical effectiveness and cost effectiveness of technologies for
mer P, Dempster DW, Nieves J, Shane E, Fratzl P, Klaushofer K, the secondary prevention of osteoporotic fractures in postmeno-

Downloaded from https://academic.oup.com/edrv/article/26/5/688/2355192 by Carol Davila University of Medicine and Pharmacy Bucharest user on 17 July 2024
Bilezikian J, Lindsay R 2003 Effects of intermittent parathyroid pausal women. www.nice.org.uk
hormone administration on bone mineralization density in iliac 86. Finkelstein JS, Hayes A, Hunzelman JL, Wyland JJ, Lee H, Neer
crest biopsies from patients with osteoporosis: a paired study be- RM 2003 The effects of parathyroid hormone, alendronate, or both
fore and after treatment. J Clin Endocrinol Metab 88:1150 –1156 in men with osteoporosis. N Engl J Med 349:1216 –1226
69. Beck TJ, Stone KL, Oreskovic TL, Hochberg MC, Nevitt MC, 87. Vahle JL, Sato M, Long GG, Young JK, Francis PC, Engelhardt JA,
Genant HK, Cummings SR 2001 Effects of current and discontin- Westmore MS, Linda Y, Nold JB 2002 Skeletal changes in rats
ued estrogen replacement therapy on hip structural geometry: the given daily subcutaneous injections of recombinant human para-
study of osteoporotic fractures. J Bone Miner Res 16:2103–2110 thyroid hormone (1–34) for two years and relevance to human
70. Lochmuller EM, Lill CA, Kuhn V, Schneider E, Eckstein F 2002 safety. Toxicol Pathol 30:312–321
Radius bone strength in bending, compression and falling and its 88. Tashjian AH, Chabner BA 2002 Commentary on clinical safety of
correlation with clinical densitometry at multiple sites. J Bone recombinant human parathyroid hormone (1–34) in the treatment
Miner Res 17:1629 –1638 of osteoporosis in men and postmenopausal women. J Bone Miner
71. Pistoia W, VanRietbergen B, Lochmuller EM, Lill CA, Eckstein F, Res 17:1151–1161
Ruegsegger P 2002 Estimation of distal radius failure load with micro- 89. Betancourt M, Wirfel KL, Raymond AK, Yasko AW, Lee J, Vassi-
finite element analysis models based on three-dimensional peripheral lopoulou-Sellin R 2003 Osteosarcoma of bone in a patient with
quantitative computed tomography images. Bone 30:842– 848 primary hyperparathyroidism: a case report. J Bone Miner Res
72. VanRietbergen B, Majumdar S, Newitt D, MacDonald B 2002 18:163–166
High-resolution MRI and micro-FE for the evaluation of changes in 90. Need AG, Horowitz M, Morris HA, Nordin BC 2000 Vitamin D
bone mechanical properties during longitudinal clinical trials: ap- status: effects on parathyroid hormone and 1,25-dihydroxyvitamin
plication to calcaneal bone in postmenopausal women after one D in postmenopausal women. Am J Clin Nutr 71:1577–1581
year of idoxifene treatment. Clin Biomech 17:81– 88 91. Chapuy MC, Preziosi P, Maamer M, Arnaud S, Galan P, Hercberg
73. Wehrli FW, Hilaire L, Fernandez-Seara M, Gomberg BR, Song S, Meunier PJ 1997 prevalence of vitamin D insufficiency in an
HK, Zemel B, Loh L, Snyder PJ 2002 Quantitative magnetic res- adult normal population. Osteoporos Int 7:439 – 443
onance imaging in the calcaneus and femur of women with varying 92. Ensrud KE, Black DM, Palermo L, Bauer DC, Barrett-Conner E,
degrees of osteopenia and vertebral deformity status. J Bone Miner Quandt SA, Thompson DE, Karpt DB 1997 Treatment with alen-
Res 17:2265–2273 dronate prevents fractures in women at high risk. Arch Intern Med
74. Wehrli FW, Saha PK, Gomberg BR, Song HK, Snyder PJ, Benito 157:2617–2624
M, Wright A, Weening R 2002 Role of magnetic resonance for 93. Mosekilde L, Danielsen CC, Gasser J 1994 The effect on vertebral
bone mass and strength of long term treatment with antiresorptive
assessing structure and function of trabecular bone. Top Magn
agents (estrogen and calcitonin), human parathyroid hormone (1–
Reson Imaging 13:335–355
38), and combination therapy, assessed in aged ovariectomized
75. Hodsman AB, Fraher LJ, Ostbye T, Adachi JD, Steer BM 1993 An
rats. Endocrinology 134:2126 –2134
evaluation of several biochemical markers for bone formation and
94. Hock JM, Hummert JR, Boyce R, Fonseca J, Raisz LG 1989 Re-
resorption in a protocol utilizing cyclical parathyroid hormone and
sorption is not essential for the stimulation of bone growth by hPTH
calcitonin therapy for osteoporosis. J Clin Invest 91:1138 –1148
(1–34) in rats in vivo. J Bone Miner Res 4:449 – 458
76. Hodsman AB, Fraher LJ, Watson PH, Ostbye T, Stitt LW, Adachi
95. Cheng PT, Chan C, Muller K 1995 Cyclical treatment of osteopenic
JD, Taves DH, Drost D 1997 A randomized controlled trial to ovariectomized adult rats with PTH (1–34) and pamidronate.
compare the efficacy of cyclical parathyroid hormone versus cy- J Bone Miner Res 10:119 –126
clical parathyroid hormone and sequential calcitonin to improve 96. Delmas PD, Vergnaud P, Arlot ME, Pastoureau P, Meunier PJ,
bone mass in postmenopausal women with osteoporosis. J Clin Nilssen MHL 1995 The anabolic effect of human PTH (1–34) on
Endocrinol Metab 82:620 – 628 bone formation is blunted when bone resorption is inhibited by the
77. Finkelstein JS, Klibanski A, Arnold AL, Toth TL, Hornstein MD, bisphosphonate tiludronate—is activated resorption a prerequisite
Neer RM 1998 Prevention of estrogen deficiency-related bone loss for the in vivo effect of PTH on formation in a remodelling system?
with human parathyroid hormone (1–34): a randomized controlled Bone 16:603– 610
trial. JAMA 280:1067–1073 97. Cosman F, Nieves J, Woelfert L, Formica C, Gordon S, Shen V,
78. Lane NE, Sanchez S, Modin GW, Genant HK, Pierini E, Arnaud Lindsay R 2001 Parathyroid hormone added to established hor-
CD 1998 Parathyroid hormone treatment can reverse corticoste- mone therapy: effects on vertebral fracture and maintenance of
roid-induced osteoporosis. Results of a randomized controlled clin- bone mass after parathyroid hormone withdrawal. J Bone Miner
ical trial. J Clin Invest 102:1627–1633 Res 16:925–931
79. Marcus R, Wang O, Sattershite J, Mitlak B 2003 The skeletal 98. Reeve J, Bradbeer JN, Arlot M, Davies UM, Green JR, Hampton
response to teriparatide is largely independent of age, initial bone L, Edouard C, Hesp R, Hulme P, Ashby JP 1991 hPTH (1–34)
mineral density, and prevalent vertebral fractures in postmeno- treatment of osteoporosis with added hormone replacement ther-
pausal women with osteoporosis. J Bone Miner Res 18:18 –23 apy: biochemical, kinetic and histological responses. Osteoporos
80. Fujita T, Inoue T, Morii H, Morita r, Norimatsu H, Orimo H, Int 1:162–170
Takahashi HE, Yamamoto K, Fukunaga M 1999 Effect of an in- 99. Kurland ES, Heller SL, Cosman F, Diamond B, Lindsay R, Bilez-
termittent weekly dose of human parathyroid hormone (1–34) on ikian JP 2001 The post-PTH experience in men with idiopathic
osteoporosis: a randomized double-masked prospective study us- osteoporosis: bisphosphonates versus non-pharmacologic therapy.
ing three dose levels. Osteoporos Int 296 –306 J Bone Miner Res 16(Suppl 1):F363 (Abstract)
81. Eli Lilly 2004 Product monograph: Forteo. Toronto, Ontario, Can- 100. Ettinger B, San Martin JA, Crans GG, Pavo I 2004 Differential
ada: Eli Lilly effects of teriparatide after treatment with ralozifene or alendro-
82. Morrissey JJ, Cohn DV 1979 Regulation of secretion of parathor- nate. J Bone Miner Res 19:745–751
mone and secretory protein I from separate intracellular pools by 101. Cosman F, Nieves J, Woelfert L, Shen V, Lindsay R 1998 Alen-
calcium dibutyryl, cyclic AMP and (1)-isoproteronol. J Cell Biol dronate does not block the anabolic effect of PTH in postmeno-
83:93–102 pausal osteoporotic women. J Bone Miner Res 13:1051–1055
83. Genant HK, Scheele WH, Sie L, Krege JH 2003 Teriparatide re- 102. Cosman F, Nieves JW, Luckey MM, Zion M, Woelfert L, Lindsay
duces the incidence of new or worsening back pain in women with R 2003 Daily versus cyclic PTH combined with alendronate versus
osteoporosis. J Bone Miner Res 18(Suppl 2):M376 (Abstract) alendronate alone for treatment of osteoporosis. J Bone Miner Res
84. Hodsman AB, Hanley DA, Josse R 2002 Do bisphosphonates re- 18 (Suppl 2):S32 (Abstract)
Hodsman et al. • PTH Therapy for Osteoporosis Endocrine Reviews, August 2005, 26(5):688 –703 703

103. Lindsay R. Scheele WH, Clancy AD, Mitlak BH 2001 Incident CD 2000 Bone mass continues to increase at the hip after parathy-
vertebral fractures during an 18-month observation period follow- roid hormone treatment is discontinued in glucocorticoid-induced
ing discontinuation of LY333334 [recombinant human parathyroid osteoporosis: results of a randomized controlled clinical trial.
hormone (1–34), rhPTH (1–34)] use in postmenopausal women J Bone Miner Res 15:944 –951
with osteoporosis. J Bone Miner Res 16 (Suppl 1):1105 (Abstract) 106. Oglesby AK, Minshall ME, Shen W, Xie S, Silverman SL 2003

Downloaded from https://academic.oup.com/edrv/article/26/5/688/2355192 by Carol Davila University of Medicine and Pharmacy Bucharest user on 17 July 2024
104. Roe EB, Sanchez SD, Cann CE, del Puerto GA, Pierini E, Arnaud The impact of incident vertebral and non-vertebral fragility frac-
CD 2000 PTH-induced increases in bone density are preserved with tures on Health-Related Quality of Life in established postmeno-
estrogen: results from a follow-up year in postmenopausal osteo- pausal osteoporosis: results from the teriparatide randomized,
porosis. J Bone Miner Res 15(Suppl 1):S193 (Abstract) placebo-controlled trial in postmenopausal women. J Rheumatol
105. Lane Ne, Sanchez S, Modin GW, Genant HK, Pierini E, Arnaud 30:1579 –1583

Erratum

The May 2005 article “Selective Progesterone Receptor Modulator Development and Use in the Treatment
of Leiomyomata and Endometriosis” by K. Chwalisz, M. C. Perez, D. DeManno, C. Winkel, G. Schubert, and
W. Elger (Endocrine Reviews 26:423– 438, 2005) contained the following errors:

On page 425, the second sentence in the paragraph subtitled “A. SPRM definition” should read as follows:
Accordingly, SPRMs represent a class of PR ligands that exerts clinically relevant tissue-selective proges-
terone agonist, antagonist, partial, or mixed agonist/antagonist effects on various progesterone target tissues
in an in vivo situation depending on the biological action studied.

On page 425, in the Leiomyoma row in Table 1, the downward arrow in the Progestins column should be removed
and placed in the SPRM column. The corrected table appears below.

TABLE 1. Comparison of major pharmacodynamic effects of progestins, PAs, and SPRMs based on studies in humans and animals

Pharmacodynamic effects Progestins PAs SPRMs

Ovary
Ovulation 2 2 (2)a,b
Estrogen secretion 2 Maintained Maintained
Progesterone secretion 2 2 2 or 3a,b
Eutopic endometrium
Endometrial bleeding Irregular (breakthrough Amenorrhea (via anovulation) Amenorrhea (via an endometrial
bleeding and effect)
spotting)
Endometrial morphology Secretory or atrophyc Weakly to strongly Nonphysiological secretory
proliferatived effect/atrophyb
Endometrial vessels Fragile Robust Robust
Thick-walled vessels commonb
Pregnant uterus
Myometrium (contractility) 2 11 No or marginal effects
Cervix No effect 11e 3
Leiomyoma 1 2 2b
Breast proliferation 1 Unknown 2
2, Inhibition; (2), partial inhibition; 1, stimulation; 3, no effect.
a
Variable effects, depending on dose and duration of treatment.
b
Human studies with asoprisnil.
c
Depending on the duration of treatment.
d
Depending on compound, dose, and duration of treatment.
e
Cervical ripening.

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serving the endocrine community.