New Drugs

Teriparatide: A Review

Elaena Quattrocchi, PharmD, and Helen Kourlas, PharmD

Pharmacy Practice Department, Arnold and Marie Schwartz College of Pharmacy and Health Sciences, Long Island
University, Brool~lyn, New Yorl~

ABSTRACT

Background: Traditionally, the management of osteoporosis in men and women has included the use of antire-
sorptive agents in combination with calcium and vitamin D supplementation. The mechanism of action of teri-
paratide is unique in that it possesses anabolic properties and therefore builds bone. Since the approval of teri-
paratide in the United States in 2002, a great deal of interest regarding its use in osteoporosis has developed.
Objectives: This article reviews the information available on the new recombinant human parathyroid hor-
mone teriparatide (hPTH [1-34]), including its clinical pharmacology, mechanism of action, pharmacokinetic
properties, clinical efficacy, safety profile, potential drug interactions, contraindications and warnings, dosage
and administration, and pharmacoeconomics.
Methods: The articles included in this review were identified through searches of PubMed and MEDLINE
(1966-December 2003) and International Pharmaceutical Abstracts (1970-December 2003). Search terms
included teriparatide, Forteo, recombinant human parathyroid hormone (1-34}, and osteoporosis. The references of
the identified articles were reviewed for additional publications. Specific product information was also obtained
from the manufacturer of teriparatide.
Results: Teriparatide has been studied in postmenopausal women with osteoporosis, drug-induced osteoporo-
sis (specifically, corticosteroid-induced osteoporosis), and men with osteoporosis. The data available from vari-
ous clinical trials have shown an increase in both bone mineral density (BMD) and bone mineral content (BMC)
with the use of teriparatide compared with placebo. One study found that women treated with the 20-1~g dose
and the 40-1~g dose were 35% and 40%, respectively, less likely to have one or more new nonvertebral fractures
compared with placebo (P = 0.02). Another study compared the use of daily teriparatide 40-1~g injections ver-
sus oral daily alendronate. Results showed that the incidence of nonvertebral fractures was significantly lower in
the teriparatide group than the alendronate group (P < 0.05). A study using 20- and 40-1~g daily injections of
teriparatide was performed in men with osteoporosis. There was a statistically significant increase in lumbar
spine BMD of 5.9% in the 20-1~g group and 9.0% in the 40-1~g group (both, P < 0.001). In the femoral neck, a
1.5% increase in BMD occurred in the 20-1~g group (P = 0.021) and a 0.9% increase in the 40-1~g group (P <
0.001). A limited number of studies are available assessing the combination of antiresorptive medications and
teriparatide; however, the available data suggest that the effects of teriparatide do not require prior stimulation
of bone resorption.
Conclusions: Teriparatide has been shown clinically to improve BMD and BMC in postmenopausal women
and in men. Because of its anabolic capabilities, teriparatide can be used as an alternative to the traditional ther-

Acceptedfor publication April 5, 2004.

Printed in the USA. Reproduction in whole or part is not permitted. 0149 2918/04/$1900

Cop7right @ 2004 Excerpta Nedica, Inc 8~

CLINICAL THERAPEUTICS®

apies that are currently available for the treatment of ride, and calcitonin (salmon). 5 All of these treatment
osteoporosis, with scheduled monitoring for adverse options inhibit osteoclast-mediated bone loss and
effects such as hypercalcemia and urinary calcium therefore reduce bone turnover, and BMD is
excretion. In 1 study, mild hypercalcemia was seen increased because bone formation is permitted and
most often 4 to 6 hours after SC injection of teri- bone resorption is inhibited. 5 With these treatments,
paratide before returning to normal. Urinary calcium the increase in BMD varies depending on the skeletal
was observed to increase by 30 mg/d (0.73 retool/d) site and the medication: however, it is generally
with teriparatide. (Clin Ther. 2004:26:841-834) <10% over 3 years. 6
Copyright © 2004 Excerpta Medica, Inc. Teriparatide ®,* also referred to as recombinant human
Key words: teriparatide, osteoporosis, bone parathyroid hormone (1-34) (hPTH [1-34]), stimulates
formation. bone formation and has anabolic properties. It was first
approved in the United States in November 2002 for
the treatment of osteoporosis in men and women.
Teriparatide became available in other countries, such
INTRODUCTION as the United Kingdom and several other countries in
Osteoporosis is a disease characterized by low bone the European Union, in April 2003.
mineral density (BMD) and structural deterioration The objective of this article was to review the
of bone tissue, which lead to bone fragility and available data on the clinical chemistry and pharma-
increased susceptibility to fractures, especially of the cology, mechanism of action, pharmacokinetic
hip, spine, and wrist. 1,2 In the United States, an esti- properties, clinical efficacy, safety profile, potential
mated 44 million people are at risk for osteoporosis, drug interactions, contraindications and warnings,
68% of whom are women. 1 According to the National dosage and administration, and pharmacoeconom-
Institutes of Health (NIH), 1 osteoporosis is responsi- ics of teriparatide. We also looked at osteoporosis
ble for >1.3 billion spine, hip, and wrist fractures in men, children, and other special populations, as
each year. In the United States today, >10 million well as the potential role of combination therapy
people have osteoporosis, 8 million of whom (80%) with teriparatide.
are women. 2 In addition, an estimated 14 million US
men have either low bone mass or osteoporosis, and MATERIALS AND METHODS
low BMD affects 1 in 2 US adults. 3 Inpatient hospital Relevant articles were identified through searches
and long-term care facility expenditures for the man- of PubMed and MEDLINE for articles published
agement of osteoporosis-related fractures is estimated from 1996 to December 2003 and of International
to be $17 billion each year. 2 Pharmaceutical Abstracts for abstracts published
Osteoporosis can be classified into 3 categories or from 1970 to December 2003. Search terms included
types. Type I, postmenopausd osteoporosis, is accelerat- teriparatide, Forteo, recombinant human parathyroid
ed bone loss beginning with the start of menopause hormone (1-34), and osteoporosis. The references of
and lasting up to 10 years if there is no intervention. the identified articles were reviewed for additional
Type II, senile osteoporosis, is related to the aging publications. Specific product information was also
process and includes a decrease in the gastrointestinal obtained from the prescribing information 7 as pro-
absorption of calcium as well as a decreased rate of vided by the manufacturer.
vitamin D activation. Type III, secondary osteoporosis,
involves either disease processes or drug-related CHEMISTRY AND PHARMACOLOGY
effects that lead to the development of osteoporosis. 4 The native hormone made by the parathyroid gland
Many pharmacologic agents are available for the chief cell is hPTH (1-84), a single-chain polypeptide
treatment of osteoporosis; however, none are related with 84 amino acids and a molecular weight of 9423
to the physiologic deposition of calcium to bone. The Da. 6 The first 34 amino acids (1-34) are the biologi-
most common treatments include calcium and vita- cally active moiety of mineral homeostasis. 6,s
min D supplementation, bisphosphonates, estrogens
(with and without progestins), raloxifene hydrochlo- *Trademark of Eli Lilly and Company (Indianapolis, Indiana).

842
 E. Quattrocchi and H. Kourlas

Teriparatide is a recombinant hPTH fragment com- mediated through binding to specific high-affinity cell
posed of the first 34 amino acids of the native surface receptors. Possible mechanisms include the
84-amino acid hPTH. Teriparatide (recombinant expression of skeletal insulin-like growth factor I (IGF-I)
DNA origin) is manufactured using a strain of and bone-forming genes, al° Evidence has shown that
Escherichia coli modified by recombinant DNA tech- teriparatide increases osteoblast birth rate and prevents
nology. 7,9 Teriparatide has a molecular weight of osteoblastic apoptosis. ~° These processes increase the
4117.8 Da, and its amino acid sequence is shown in number of osteoblasts and the rate of new bone forma-
the figure. 7 tion, and prolong osteoblast survival, a~°

PARATHYROID HORMONE PHARMACOLOGY Anabolics Versus Antiresorptives

Parathyroid hormone (PTH) (1-84) is the principal Anabolic agents, such as fluoride, strontium,
regulator of calcium homeostasis in mammals. ~° PTH growth hormone IGF-I, and teriparatide directly
is released when calcium levels decrease, and it is sup- stimulate bone formation, unlike the antiresorptive
pressed when calcium levels increase. PTH regulates agents, which inhibit osteoclast-mediated bone loss
bone metabolism. It stimulates 1 alpha-hydroxylase and thus reduce bone turnover. 5,1° The antiresorp-
activity in the kidney, thereby increasing serum 1,25- tires (estrogen, raloxifene, bisphosphonates, and cal-
dihydroxyvitamin D levels, which promotes intestinal citonin) could be considered "antiremodeling" drugs
calcium absorption. In severe primary hyperparathy- because they reduce the remodeling space and pro-
roidism, the continuous exposure to PTH results in a long the duration of mineralization. 5 All of the antire-
catabolic effect on the skeleton, but when administered sorptives can increase BMD and can reduce the risk
in a low-dose (20 gg/d), intermittent fashion, it has an for new fractures, but they are generally not associat-
anabolic propert~ 5 Low-dose, intermittent PTH ed with dramatic increases in bone mass. 1° The
induces the osteoblasts to produce certain cytokines, action of antiresorptive agents to reduce fracture risk
which may explain the differences in biologic effects is rarely >50% of the baseline risk1°; rather, they pri-
between low-dose, intermittent PTH and continuous marily stabilize bone mass and prevent further bone
administration of PTH. 1° The underlying molecular loss. The potential for anabolic agents to improve
physiology accounting for the anabofic effect of PTH is BMD more substantially than the antiresorptives sug-
unknown. 1° According to the prescribing informa- gests that the former might reduce fracture risk to a
tion, 7 the biologic actions of PTH and teriparatide are greater extent than the latter. 5

I 5 10

H-

Figure. Amino acid sequence of teriparatide. Reproduced with permission. 7

843
CLINICAL THERAPEUTICS®

PHARHACOKINETIC PROPERTIES the daily recommended intake of vitamin D is 400

Teriparatide reaches peak serum concentration at - 3 0 to 800 IU.
minutes after SC injection (for a 20-lag dose) and BMD of the lumbar spine, proximal femur, radius,
decreases within 3 hours. The absolute bioavailability and the total body was measured using dual-energy
of teriparatide is -95%. 7 The systemic clearance of x-ray absorptiometry (DXA). BMD of the spine was
teriparatide (-62 Uh in women and - 9 4 Uh in men) measured at baseline, 12 and 18 months, and at
exceeds the rate of normal hepatic plasma flow, con- study end (24 months) in all women, and at 3 and 6
sistent with both hepatic and extrahepatic clear- months in a subgroup of women. BMD of the hip was
ance. 7,11 The volume of distribution after IV injection measured at baseline and at 12 and 24 months in all
is -0.12 L/kg; volume of distribution for SC injection of the women, and BMD of the forearm and the total
has not been assessed. 7,11 The serum distribution half- body was measured in only a subgroup at baseline,
life of teriparatide is 5 minutes when administered by 12 months, and at study end. Height was measured
IV injection and -1 hour when administered by SC in all patients at baseline and 12 months. Blood
injection. 7 Our review of the literature indicated no counts and urinalysis were performed in all patients
metabolism or excretion studies performed with teri- at baseline and at 1, 6, 12, and 24 months. 12
paratide; however, peripheral metabolism of PTH is A positive change in BMD was found to have
believed to occur by nonspecific enzymatic mecha- occurred from baseline to 24 months in both teri-
nisms in the liver and excretion by the kidneys. 7 paratide groups but not in the placebo group. 12
Results were statistically significant in all skeletal
CLINICAL EFFICACY measurements (all, P < 0.001), except for the distal
Neer et a112 conducted the first clinical trial that sup- radius in both teriparatide groups compared with
ported the use of teriparatide in postmenopausal placebo, and the shaft of the radius in the teriparatide
women with a history of fracture. The study was a 20-lag group compared with placebo. Of 1326
randomized, placebo-controlled trial in 1637 post- women who had radiographs available for analysis,
menopausal women (mean age, 69 years) with prior 105 women (7.9%) had .>1 new vertebral fracture.
vertebral fractures. It took place in 99 centers in 17 There was a 65% decrease in the risk for fracture in
countries for 21 months. The study was conducted to patients receiving teriparatide 20 tag and a 69%
determine whether daily injections of teriparatide decrease in patients receiving teriparatide 40 lag (P <
would increase bone formation without causing 0.001). 12 The risk for _>2 fractures was reduced by
hypercalcemia. 77% in patients receiving teriparatide 20 lag and by
Women were excluded from the study if they had 86% in patients receiving teriparatide 40 lag (P <
impaired hepatic function, which was not further 0.001). 12 Lastly, the risk for _>1 moderate to severe
classified by the study investigators; renal impair- fracture was reduced by 90% in the teriparatide
ment, characterized as a serum creatinine concentra- 20-lag group and by 77% in the teriparatide 40-lag
tion >2 mg/dL; or any illness that might affect bone group (P < 0.001). 12
and/or calcium metabolism. Women were also Zanchetta et a113 conducted a cross-sectional study
excluded if they had received any drug within the of 101 postmenopausal women, a subgroup of the
previous 2 to 24 months that would alter bone international fracture prevention trial that was origi-
metabolism, such as bisphosphonates, calcitonin, nally conducted by Neer et al. 12 These patients had
and estrogen supplementation.12 originally consented to peripheral quantitative com-
Eligible women were randomized to receive teri- puted tomography (pQCT) testing and had usable
paratide 20 or 40 lag or placebo, SC QD for 24 scans. The objective of the study was to assess the
months. 12 In addition to the study protocol, all effects of teriparatide on cortical bone from pQCT
women received daily oral supplements of calcium scans that were obtained from the subgroup of the
1000 mg and vitamin D 400 to 1200 IU. 12 The prevention trial.
National Academy of Sciences and the National Women were randomized to receive teriparatide
Osteoporosis Foundation recommend daily calcium 20 lag (n = 38) or 40 lag (n = 28) or placebo (n =
intakes of 1000 to 1200 mg for adults. 1 In addition, 35). 13 Baseline demographic variables were similar

844
 E. Quattrocchi and H. Kourlas

between all 3 groups, and no significant differences 15% reduction in vertebral height (P = 0.04). The use
in the quality of the pQCT scans were found of hPTH (1-34) was associated with an increase in
between the 3 groups. total body BMD (P = 0.002), with no negative effects
The pQCT variables were examined and analyzed; at any skeletal site. It has been suggested 15 that hPTH
statistically significant results occurred for total bone (1-34) may increase vertebral bone mass at the
mineral content (BMC), total bone area, and corti- expense of cortical bone by inducing increased intra-
cal bone area in women receiving teriparatide 20 or cortical and perhaps endocortical-junction remodel-
40 l~g compared with placebo (all, P < 0.0~). 13 Use of ing, leading to weakened bone at primarily cortical
teriparatide in this subgroup was associated with sites. However, Lindsay et a115 found little evidence
improved quality of nonvertebral cortical bone and to support this hypothesis because they found no
favorable changes in the distribution and geometry of decrease in bone mass in any skeletal site.
nonvertebral cortical bone. Roe et a116 also studied hPTH (1-34) and HRT
(conjugated equine estrogens) in postmenopausal
COMBINATION THERAPY women with osteoporosis receiving HET for _>1 year
The ideal treatment for osteoporosis would increase before study entry Seventy-four postmenopausal
bone mass, improve bone architecture and strength, women were randomized to receive hPTH (1-34)
and reduce the risk for fracture. Antiresorptive medica- 400 IU SC QD or placebo while continuing to receive
tions reduce the risk for osteoporotic fracture, but stable doses of conjugated equine estrogens (control
many osteoporotic fractures occur despite treatment. H group). A total of 60 subjects (81%) completed the
The use of teriparatide alone stimulates bone forma- treatment phase. At 24 months, the investigators
tion and increases bone mass, thereby reducing the found a 29.2% increase in spinal BMD and an 11.0%
risk for osteoporotic-related fractures. Based on our fit- increase in femoral BMD as measured by DXA in
erature review, limited data are available on the use of women receiving combination therapy, compared
teriparatide in combination with other therapeutic with 0.9% and 0.2%, respectively, in the control
options for the treatment of osteoporosis, hPTH (1-34) group (both, P < 0.001). Of patients who were ran-
agents, including teriparatide, have been studied in domized to hPTH (1-34) and who underwent DXA
combination with other medications for the treatment scanning at 24 months, 89% had increases in lumbar
of osteoporosis, H-23 but data are still limited. spine BMD >2 SDs. Trabecular BMD in L1-L2, as
A few studies 15-17 have used recombinant hPTH measured by quantitative computed tomography
(1-34) in combination with hormone replacement (QCT), increased in the hPTH group by a median of
therapy (HRT). Lindsay et a115 performed a B-year, 74% from baseline to 24 months (P = 0.027) and
randomized, controlled trial of hPTH (1-34), 400 IU decreased 2.1% in the placebo group (P = NS). These
SC QD, in 17 postmenopausal women with osteo- findings indicate combination therapy is effective in
porosis receiving HRT (conjugated equine estrogen producing large increases in BMD at the lumbar spine
[0.62~ mg/d] or transdermal estrogen [~0 l~g,'d]) and and femoral neck, ~6 and that therapy with hPTH
medroxyprogesterone acetate ~-10 mg for 10 days or (1-34) might restore bone mass above the osteopenic
2.~ mg/d continuously. Patients who had a hysterec- range in postmenopausal women with osteoporosis.
tomy did not receive a progestin (n = 6). The controls Cosman et al ~7 investigated the use of hPTH (1-34)
were women receiving HRT only (n = 17). In patients in combination with established HRT for 22 years in
receiving HRT and hPTH (1-34), the total increases 52 women with osteoporosis, and its effects on verte-
in BMD were 13.0% in the vertebrae (P < 0.001), bral fracture and maintenance of bone mass after PTH
2.7% (P = 0.0~) in the hip, and 8.0% (P = 0.002) in withdrawal. Women included in the PTH and HRT
the total bod)~ No significant changes in BMD were group had a mean age of 57.7 years, and the women
found at any site in the control group. The women who received HRT alone had a mean age of 62.9
receiving combination treatment had fewer vertebral years. Twenty-seven women were randomly assigned
fractures than controls. Increased BMD was associat- to remain on hPTH (1-34) 400 IU SC QD plus HRT,
ed with a reduction in the rate of vertebral fractures, and 25 women were to remain on HRT alone (control
which was significant when fractures were taken as a group), for 3 years. In the control group, BMD and

845
CLINICAL THERAPEUTICS®

biochemical variables of bone turnover remained sta- (calcium carbonate 1500 mg/d) and a vitamin D sup-
ble throughout the 3-year treatment trial and 1-year plement (800 IU/d), provided as 2 multivitamins. All
follow-up. Women in the combination-therapy group study patients were maintained on their individual
had mean (SD) increases in bone mass of 13.4% HRT regimen (not specified), and had been receiving
(1.4%) in the spine, 4.4% (1%) in the total hip, and HRT for >1 year. Patients were continued on their glu-
3.-/% (1.4%) in the total b o @ Percentage changes cocorticoid regimen. The mean daily dose of the glu-
in BMD of the lumbar spine, total hip, and total cocorticoid was similar between groups at baseline
body were significantly different in the combination- through study end.
therapy group compared with baseline and the group Patients were taught SC self-injection, but placebo
receiving HRT alone (both, P < 0.05). The rates of injections were not used. A mean dose of 25 l~g
increase were most prominent in the first 6 to 12 (400 U) SC QD was given for 12 months.
months of treatment. BMD measurements remained The BMD of the lumbar spine, measured us-
stable 1 year after discontinuation of hPTH (1-34) ing QCT and DXA, increased significantly in the
treatment, without any significant loss while women combination-therapy group (P < 0.001) after 12
continued HRT. Therapy with hPTH (1-34) was asso- months of treatment, whereas it remained the same in
ciated with a reduced incidence of vertebral fracture the group receiving estrogen only. The mean differ-
of 75% to 100% compared with HRT alone. The inci- ences between the treatment groups at 12 months
dence of vertebral fractures was assessed over 3 years were 33.5% for the lumbar spine by QCT (P < 0.001)
of the study using decreases in vertebral heights of and 9.8% by DXA (P < 0.001).
15% or 20% compared with vertebral heights on the Women in the hPTH (1-34)-plus-HRT group
baseline radiograph. In the 15% reduction criterion, experienced mean (SD) increases of 35% (5.5%) in
there were 2 vertebral fractures in the PTH-plus-HRT vertebral BMD as measured using QCT, and 11%
group compared with 12 vertebral fractures in (1.4%) as measured by DXA scan, compared with rel-
patients receiving HRT alone (P = 0.001). In the 20% atively small changes of 1.7% (1.8%) and 0% (0.9%),
reduction criterion, there were no vertebral fractures respectively, in the estrogen-only group. After 12
in the PTH-plus-HRT group and 7 vertebral fractures months of hPTH (1-34) administration, no signifi-
in patients receiving HRT alone (P = 0.003). Using cant changes in BMD were found in the hip or fore-
the 15% height reduction cutoff point, PTH was asso- arm between or within the groups. According to the
ciated with a reduction in the percentage of women investigators, 19 although the anabolic effects of PTH
who had incident vertebral fractures, from 3-/.5% to were significantly less or absent in the hip and fore-
8.3% (P < 0.02). Using the 20% height reduction cut- arm region, no negative effect of PTH was found after
off point, PTH was associated with a reduction in the 12 months at these sites, as has been previously
percentage of women who had incident vertebral reported, is
fractures, from 25.0% to 0.0% (P = 0.02). is Lane et al is conducted another study to determine
The most common cause of drug-related osteoporo- whether changes in bone turnover and bone mass
sis is the use of glucocorticoids, 1° which are associat- would occur during the 12 months after hPTH
ed with rapid bone loss, fractures, increased morbid- (1-34) treatment was discontinued. The mean (SD)
ity,5 suppression of bone formation, and increased change in BMD of the lumbar spine, as assessed using
bone resorption. 24 Lane et al > conducted a 12-month QCT and DXA scans, in the PTH group at 24 months
randomized clinical trial of hPTH (1-34) in 51 post- was 45.9% (6.4%) and 12.6% (2.2%), respectively
menopausal women (mean age, 63 years) who were (P < 0.01). After 12 months of follow-up, a significant
receiving HRT and corticosteroids (>5 mg/d of pred- increase from baseline in hip bone mass was observed
nisone) for a chronic inflammatory disease for >1 year (change, 4.7% [0.9%]; P < 0.01). According to Lane
before the study, and planned to continue therapy for et al, ~s the additional increases in BMD that occur
>1 year. The women were randomly assigned, using a after discontinuing hPTH (1-34) for 12 months may
compute>generated randomization table, to receive be the result of filling in of the remodeling space that
hPTH (1-34) plus estrogen (n = 28) or estrogen alone was excavated in response to the study drug treat-
(n = 23). Patients were given a calcium supplement ment. The delayed increase in BMD may also be due

846
 E. Quattrocchi and H. Kourlas

to the fact that a DXA scan cannot measure the The effect of combining antiresorptives and recom-
increase until the newly formed bone matrix becomes binant hPTH (1-34) must still be studied. If bisphos-
fully mineralized, which requires several months, is phonates stay bound to bone and continue to inhibit
The results of both studies suggest that PTH increas- bone formation for years after treatment is discontin-
es bone mass in the lumbar spine and hip in post- ued, it may be best to give hPTH (1-34) alone before
menopausal women with glucocorticoid-induced starting bisphosphonates, xl A randomized controlled
osteoporosis who are receiving HRT. The maximal trial was performed by Rittmaster et al xx in 66 post-
effect on bone mass at the hip required an additional menopausal osteoporotic women aged 50 to 75 years
6 to 12 months after hPTH (1-34) was discontinued. to assess the effects of PTH (1-84) followed by alen-
Also, the investigators found no evidence of cortical dronate. The women with osteoporosis were treated
bone remodeling that has been reported is in animals for 1 year with recombinant hPTH (1-84) 50, 75, or
treated with hPTH (1-34) and in primary hyper- 100 ug SC QD or placebo, and then were given alen-
parathyroidism. Lane et al ls,19 concluded that estro- dronate 10 mg PO QD for an additional year. BMD
gen in combination with hPTH (1-34) might have was measured in the femoral neck, lumbar spine, and
reduced cortical bone remodeling. the total body: In all women receiving hPTH (at any
Rehman et al 2° conducted a follow-up study to dose), mean (SD) changes in BMD were 7.1% (5.6%)
determine whether hPTH (1-34) use is associated (spine), 0.3% (6.2%) (femoral neck), and -2.3%
with an increase in vertebral cross-sectional BMD in a (3.3%) (total body). Patients who had originally
group of postmenopausal women with glucocorticoid- received 100 or 75 ug of PTH had a greater improve-
induced osteoporosis. They hypothesized that if ment in BMD than those who had received placebo
hPTH (1-34) increases bone formation in the (P < 0.001, P < 0.004 for the 100- and 75-ug patients,
periosteal surface, this will increase vertebral size, respectively).22 In women who received hPTH (1-84),
and that the increased vertebral size could improve after switching to alendronate for 1 year, the mean
bone strength. Fifty-one postmenopausal women (SD) changes in BMD were 13.4% (6.4%) (spine),
receiving chronic stable doses of HRT (conjugated 4.4% (7.2%) (femoral neck), and 2.6% (3.1%) (total
estrogens, 0.625 mg PO QD for >1 year) and gluco- body). This study provides evidence that prescribing a
corticoid therapy (prednisone, mean dose, 5-20 mg bisphosphonate, such as alendronate, after a course of
PO QD for >1 year) who had osteoporosis (defined as hPTH (1-84) results in greater increases in spinal
a t score <-2.5 SDs at the lumbar spine and/or hip) BMD than prescribing alendronate alone. 22,23
were included. 2° Twenty-eight women were random- A short-term study of 10 postmenopausal women
ized to receive hPTH (1-34) 40 ug SC QD for 12 with osteoporosis was conducted by Cosman et a114
months with a 12-month follow-up while continuing to determine whether hPTH (1-34) in combination
to receive HRT, and 23 received placebo and HRT for with alendronate could be a viable treatment for
24 months. Baseline QCT scans were performed at L1 osteoporosis. Patients were assigned in an open fash-
and L2. Vertebral cross-sectional area (VCSA) of L1 ion to PTH plus alendronate (mean [SD] age, 69 [1.8]
and L2 were measured for each lumbar spine QCT years) or alendronate alone (mean [SD] age, 64 [4.8]
scan at baseline and at 12 and 24 months. Patients years). Five patients continued receiving alendronate
who received hPTH (1-34) plus HRT had a 4.8% 10 mg/d alone and 5 patients continued receiving
increase in L1 and L2 in the VCSA (P < 0.001). alendronate with hPTH (1-34) 400 IU SC QD added
During follow-up (ie, 12 months after hPTH was dis- for 6 weeks. The data showed that hPTH (1-34)
continued and patients had continued with HRT), could increase biochemical indicators of bone forma-
VCSA increased from baseline by 2.6% (P < 0.05). 20 tion in the presence of pretreatment with alen-
Alternatively, no significant differences in VCSA dronate. Markers of bone formation increased within
occurred at 12 or 24 months in the group receiving 3 weeks in the hPTH-plus-alendronate group, with
HRT and placebo. The increase in vertebral compres- mean peak levels at 5 to 7 weeks: osteocalcin, 49%
sion strength was estimated to be >200%; however, (P < 0.01); propeptide of type I procollagen, 61%
this increase was a result of increased BMD rather (P < 0.01); and bone-specific alkaline phosphatase
than an increased VCSA. (ALP), 24% (P = NS). No significant changes occurred

847
CLINICAL THERAPEUTICS®

at any time in the alendronate group, which suggests were instructed to continue supplementation after
that the anabofic effect of hPTH (1-34) does not randomization.
require prior stimulation of bone resorption and that Patients were randomized to receive either hPTH
bone formation must be preceded by bone resorp- (1-34) 400 IU SC QD (equivalent to 23 ug/d) (n =
tion. The NIH is sponsoring a randomized trial to 10) or placebo (n = 13). 26 Compliance was measured
determine whether combination treatment with using medication diaries and vial counts. BMD of the
hPTH (1-34) and a bisphosphonate is better or worse lumbar spine, right hip, and nondominant radius was
than or no different from sequential therapy measured using DXA every 6 months after initiation
of treatment. Additional testing included serum calci-
SPECIAL P O P U L A T I O N S um, phosphorus, alkaline phosphatase activity, albu-
Osteoporosis in Men min, blood urea nitrogen, and creatinine levels. These
In the United States, ~3% of men aged >30 years tests were performed during enrollment, at 1 month,
have osteoporosis, and -30% of men aged >30 years and every 3 months thereafter.
have osteopenia. 1 The prevalence of osteoporosis is Patients who received hPTH (1-34) had a statisti-
greater in white men (7%) than in black (3%) and cally significant increase in BMD at the lumbar spine
Hispanic American (3%) men, based on the data cur- compared with those who received placebo (P <
rently available. 25 Information on the rates of osteo- 0.001), with a mean (SD) increase of 13.5% (3.0%) at
porosis in Asian American men and other ethnic 18 months. In addition, mean (SD) BMD in the
groups is still lacking. 25 The development of osteo- femoral neck was significantly increased--2.9% (1.5)
porosis in men is primarily related to various factors at 18 months (P < 0.05)--in the treatment group as
that can include hypogonadism, hyperparathy- compared to the placebo group. Lastly, in men who
roidism, long-term glucocorticoid use (ie, predni- were treated with hPTH (1-34), the mean (SD) lum-
sone _>3 mg for >6 months), excessive alcohol use bar spine t score did not improve statistically signifi-
(22 drinks/d), family history, and possibly anticon- cantly (from -3.5 [0.2] to -2.4 [0.4]). One a score
vulsant therapy with phenytoin and phenobarbital. unit improvement was observed in the lumbar spine
Current treatments of osteoporosis in men include (P < 0.003), however. 26 No statistically significant
calcium and vitamin D supplementation and the use changes in t or a scores were found in the femoral
of bisphosphonates. Teriparatide is now indicated as neck or the radius.
another potential treatment option. 26,27 Kurland et a126 found that low-dose administration
Kurland et al 2° conducted one of the first random- of hPTH (1-34) increased BMD in men over the 18-
ized, double-blind, placebo-controlled trials to assess month trial period. The study allows further investi-
the use of hPTH (1-34) in men with osteoporosis. gation of the use of hPTH in men with osteoporosis,
The 18-month study involved 23 patients with idio- Orwoll et a127 conducted one of the first randomized
pathic osteoporosis (mean [SD] age, 30 [1.9] years). studies using teriparatide in men. Patients were
Patients were included if they had a t score of <-2.3 recruited from hospital clinics and community prac-
SD at the lumbar spine or femoral neck. Measures tices from 37 centers in 11 countries.
were taken to exclude individuals with known sec- Men were included in the study if they were ambu-
ondary causes of osteoporosis, even though men with latory; flee of any chronic, disabling conditions other
hypogonadism were included if they had been on a than osteoporosis; had a BMD 2-2.00 SD at the lum-
stable dose of testosterone for at least 2 years before bar spine or proximal femur; and were stable for 26
the start of the study Doses of testosterone were months before randomization. Men were excluded if
not provided in the study. Patients were also allowed they had secondary causes of osteoporosis, including
to receive medications for the management of osteo- having received any type of medication that would
porosis before but not within 6 months of ran- affect bone metabolism (eg, glucocorticoids, estrogen
domization. Prior to randomization, there was a 12- agonists and antagonists, anticonvulsants, calcium, or
to l % m o n t h observational period before which all aluminum-containing antacids); if they had any dis-
patients were instructed to have a total daily intake of ease or disease process that would affect calcium
calcium 1300 mg and of vitamin D 400 IUi patients absorption or excretion; or if they had been treated

848
 E. Quattrocchi and H. Kourlas

with calcitonin, bisphosphonates, progestins, fluo- Teriparatide treatment was associated with an
rides, vitamin D, or any type of anabolic steroid with- increase in osteoblast activity compared with placebo
in 6 months of the start of the study. Men receiving after 1 month (P < 0.001) as assessed using ALP and
exogenous androgen formulations (eg, testosterone) PICP measurements. Biochemical markers for bone
were not excluded. formation peaked after 6 to 12 months of treatment
Bone markers (ie, bone ALP and serum procollagen I with teriparatide use. The markers for bone resorp-
carboxy-terminal propeptide [PICP] for bone forma- tion were stable in the placebo group; however, they
tion; and urinary N-telopeptide/creatinine ratio and free increased in both teriparatide groups. However, the
deoxypyridinoline/creatinine ratio for bone resorption) study did not assess the risk for fracture in male
were measured at baseline and at 1, 3, 6, and 12 patients with osteoporosis. Compliance was based on
months. The primary objective of the study was to the mean percentage of study medication taken in
assess changes in BMD of the lumbar spine from base- each group, which was 79%. 2r
line to study end. Median duration of follow-up was 11 According to the teriparatide prescribing informa-
months. Secondary end points included changes in tion] no age-related pharmacokinetic differences in
BMD of the total hip, femoral neck, intertrochanter, teriparatide have been found in patients ranging in
trochanter, radius, and the total body, and BMC of the age from 31 to 85 years. Teriparatide has been stud-
total body, from baseline to study end. Compliance was led in the geriatric population (>65 years of age) in
measured by counting the number of unused synnges clinical trials, with no significant difference in bone
returned at scheduled visits. response or adverse reactions compared with
Of the 959 men originally screened (age range, younger patients (<65 years of age)7 Elderly patients
30-85 years), 437 were eligible. Of these, 151 men in general, however, may be more sensitive to med-
received teriparatide 20 l~g/d, 139 received teriparatide ications overall. According to the prescribing infor-
40 l~g/d, and 147 received placebo. All baseline cha> mation, s the recommended dosage for both men and
acteristics were similar between the 3 study groups. women is 20 l~g,'d, even though systemic concentra-
This study 27 showed several statistically significant tions of teriparatide are 20% to 30% lower in men
differences in BMD and BMC in some selected skele- than in women.
tal measurements. BMD was increased, with mean
changes from baseline to end point of 5.9% (P < Children
0.001) in the lumbar spine, and 1.5% (P = 0.029) in The pharmacokinetic trials of teriparatide by the
the femoral neck in patients receiving teriparatide manufacturer were performed in a population that
20 l~g/d compared with placebo. Patients who was 98.5% white; therefore, the role of race in teri-
received teriparatide 40 l~g,'d experienced mean paratide pharmacokinetic properties cannot be deter-
changes from baseline to end point of 9% (P < 0.001) mined because of the limited data available. 7 Also,
in the lumbar spine and 2.9% (P < 0.001) in the teriparatide pharmacokinetic data have not been
femoral neck compared with placebo. In addition, assessed in the pediatric population] so no informa-
teriparatide 40 l~g/d was associated with a mean tion in this special population can currently be pro-
change in BMD of 2.3% in the intertrochanter and the vided. However, it is known that teriparatide should
total hip compared with placebo (P < 0.001 for both not be used in children (2-12 years of age) 2s or
comparisons). Lastly, a dose-dependent change was young adults (13-18 years of age) 2s with open epi-
found between the teriparatide 20-1~g,'d and 40-1~g,'d physes. In 1 case report, a 16-yea>old female adoles-
groups in the lumbar spine (P < 0.001), femoral neck cent with autoimmune hypoparathyroidism and
(P = 0.023), intertrochanter (P = 0.012), and total hip osteoporosis received hPTH (1-34) for 6 months. 29
(p = 0 . 0 0 9 ) . The patient was diagnosed with hypoparathyroidism
Total-body BMC increased 0.6% in the teriparatide at age 9 years and with osteoporosis at age 15 years,
20-tag/d group versus placebo (P = 0.021), and 0.9% 10 years after vertebral compression fractures were
in the teriparatide 40-tag/d group versus placebo (P = noted on plain radiography of the spine. > Treatment
0.005). No significant differences were found between was initiated with hPTH (1-34) 80 l~g SC QD for
the 20- and 40-tag/d groups in total-body BMC. 3 months, then 32 l~g BID for 3 additional months.

849
CLINICAL THERAPEUTICS®

DXA scanning showed a 23% increase in lumbar and primates. PTH stimulates longitudinal bone
spine BMD after 6 months; at that point, treatment growth in rats throughout most of their lives. In
with hPTH (1-34) was concluded. However, contin- humans, longitudinal skeletal growth ceases by 18 to
ued improvement was seen 6 months after treatment 24 years of age. ° The human skeleton is dominated
discontinuation. 29 Additional studies need to be con- by osteonal remodeling, and the rat skeleton is dom-
ducted to fully understand the response to hPTH inated by skeletal growth modeling. In rats, PTH
(1-34) in adolescents and to determine the long-term increases cortical bone mass by layering new bone on
effects of the drug on growth and development in this old bone. The effect that occurred in these Fischer
population. 344 rats was highly dependent on the dose; duration;
and, perhaps, the time in a rat's life cycle that the drug
Pregnant Patients was administered. Basically, these Fischer 344 rats
Teriparatide should not be used in pregnant were administered nearly lifetime daily injections of
women. Teriparatide has not been studied in human PTH. Lastly, regarding the physiologic component of
fetal development and is pregnancy category C. No the rat skeleton, it consistently grows throughout the
clinical data are available to determine whether rat's life span, and Fischer rats have historically been
teriparatide is secreted into breast milk. Thus, the at risk for developing osteocarcinoma without the
drug also should not be used in women who are administration of exogenous parathyroid. ° This may
breastfeeding. further explain the overwhelming development of
osteocarcinoma in parathyroid-treated Fischer 344
Comorbidity rats. Therefore, per Tashjian and Chabner, ° their find-
All clinical trials assessing teriparatide have exclud- ings cannot predict an increased risk for osteosarco-
ed individuals with renal insufficiency, hepatic in- ma in patients with osteoporosis receiving teri-
sufficiency, and heart failure. Therefore, use of teri- paratide therapy for _<2 years. The safety and efficacy
paratide is limited to otherwise healthy patients. 7,H of teriparatide have not been studied beyond 2 years
of treatment; therefore, use of this drug for >2 years
SAFETY A N D TOLERABILITY is not recommended. 9
Carcinogenesis In the study conducted by Neer et a112 in 1637
Concerns exist regarding the safety of teriparatide. women receiving either hPTH (1-34) 20 or 40 l~g SC
As part of drug testing, teriparatide was given to rats QD or placebo for a median period of 18 months, no
for a significant part of their lifetime, and studies evidence of osteocarcinoma was found. Cancer devel-
demonstrated an increased risk for osteosarcoma, a oped in 40 patients (2% in each hPTH [1-34] group
rare but serious malignant primary bone tumor. 7,° and 4% in the placebo group). However, the types of
Osteosarcoma is a spindle cell neoplasm that pro- cancer that developed in the 40 women were neither
duces osteoid (unmineralized bone) or bone that identified nor explained.
spreads by local invasion to adjacent tissues and to In the study by Kurland et al, 26 of the 10 patients
distant sites, such as the lungs. 7,3°-32 It is neither a who were randomized to receive hPTH (1-34) 400 IU
carcinoma nor a metastatic cancer from other primary SC QD (equivalent of 25 l~g/d), there was no report-
tumors. A study conducted by Tashjian and Chabner ° ed documentation of any form of bone-related can-
showed that a 2-year rat bioassay, using Fischer 344 cer. °,32 Similarly, in the study by Orwoll et al, 27 after
rats, resulted in the development of osteocarcinoma. the median treatment duration of 11 months, no evi-
The incidence depended on the doses that were dence of osteocarcinoma was found.
administered, which included 5, 30, and 75 t~g/kg.d No information is available assessing the safety of
given to 6- to 8-week-old rats. The highest incidence teriparatide in patients with hepatic, renal, or cardiac
(48%) of osteocarcinoma, therefore, developed in the disease. 7
animals that received 73 Ug/kg.d. 9 However, the find-
ings cannot be extrapolated to humans for various Other Adverse Events
reasons, one of the most important of which is the Adverse drug events (ADEs) that have been associat-
differences in skeletal physiology between rodents ed with teriparatide use include angina pectoris,

850
 E. Quattrocchi and H. Kourlas

asthenia, constipation, depression, dizziness, headache, In the study conducted by Neer et al, 12 94 of the
hypercalcemia, hypertension, hyperuricemia, in- 1637 women (6%) withdrew because of ADEs.
somnia, nausea, neck pain, syncope, and vertigo. 7,n Eighteen percent of the women reported nausea, 13%
According to the prescribing information, 7 when teri- headache, 9% dizziness, and 3% leg cramps. In the
paratide 20 l~g is administered once daily, the serum study by Body et al, 24 6 patients (8.2%) receiving ted-
calcium concentration increases transiently, begin- paratide and none receiving alendronate reported leg
ning - 2 hours after dosing, reaching a maximum con- cramps. Twenty-eight women (38.4%) receiving ted-
centration between 4 and 6 hours (median increase, paratide and 2 (3%) receiving alendronate had elevated
0.4 mg/dL), decreasing - 6 hours after dosing, and serum calcium levels at least once within 4 to 6 hours
returning to baseline values by 16 to 24 hours after after dosing, n , n The elevated serum calcium levels
dosing. 7 were not associated with clinically significant adverse
Neer et a112 reported that mild hypercalcemia outcomes, and the women were asymptomatic.
(defined as a calcium concentration >10.6 rag/alL)
developed in 28% of women receiving hPTH (1-34) DRUG INTERACTIONS
40 l~g/d and in 11% of women receiving hPTH Limited data are available on the use of teriparatide
(1-34) 20 l~g/d 16 to 24 hours after previous injec- and other concurrent medications. One available
tion. Persistent hypercalcemia was not observed in study analyzed the coadministration of oral hydro-
clinical trials of teriparatide, nor in the study by Neer chlorothiazide 25 mg in 20 healthy subjects. 7
et al. ~2 If persistent hypercalcemia is detected, ted- Teriparatide 40 Pg did not affect serum calcium lev-
paratide should be discontinued and the patient els. In addition, a study of 17 patients with mild,
should be assessed for the cause of the hypercal- moderate, or severe hypercalcemia and 9 healthy
cemia. The prescribing information 7 does not recom- subjects was conducted with the coadministration
mend that patients with underlying hypercalcemic of furosemide 20 to 100 mg IV QD and teriparatide
disorders, such as hyperparathyroidism, be treated 40 Pg SC QD. No clinically significant increases in
with teriparatide. Teriparatide increases urinary calci- serum calcium were found. 7
um excretion, but the frequency for hypercalciuria Because teriparatide can transiently increase serum
in clinical trials is similar between teriparatide calcium levels, caution should be exercised when
and placebo. 7 concomitantly administering teriparatide and digital-
In clinical trials, 2.8% of teriparatide-treated is. In a study 33 conducted in 15 healthy subjects,
patients had serum uric acid concentrations above the administration of teriparatide 40 l~g SC QD, added to
upper limit of normal compared with 0.7% of patients digoxin already at steady state, did not alter the effect
receiving placebo. 7 No significant increases in gout, of the digoxin. It has been suggested that hypercal-
arthralgia, or urolithiasis were found in the study cemia may predispose patients who are receiving digi-
patients. Teriparatide has not been studied in patients talis to toxicity, and caution and frequent monitoring
with active urofithiasis and should be used with are recommended. 33
caution in patients with active or recent urolithiasis
because of the potential to exacerbate the condition. 7 CONTRAINDICATIONS AND WARNINGS
Limited information is available to assess the safe- Osteosarcoma in humans occurs in a bimodal age dis-
ty of teriparatide in patients with hepatic, renal, or tribution, with 1 incidence peak during late adoles-
cardiac disease. According to the prescribing infor- cence and young adult life (age 13-25 years), and the
mation, 7 short-term clinical pharmacology studies other occurring in the 6th decade and beyond. 31,32
showed infrequent but transient episodes of symptom- This bimodal incidence is related to the intrinsic state
atic orthostatic hypotension. The episodes typically of bone turnover during these 2 periods. The inci-
occurred within the first several doses and within dence is also increased in men and women who have
4 hours of dosing, and resolved within a few minutes Paget's disease of bone later in life or who have under-
to a few hours. The transient orthostatic hypotension gone radiotherapy of the skeleton. 34,35
did not preclude continued use of teriparatide in Due to the uncertain relevance of the rat osteosar-
these patients. coma findings to humans, the manufacturer of ted-

851
CLINICALTHERAPEUTICS®

paratide has placed a "black box" warning in the teriparatide shortly after taking the pen out of the
package insert indicating that teriparatide should be refrigerator. The pen should be recapped and
prescribed only to patients in whom the potential returned to the refrigerator immediately after use.
benefits are considered to outweigh the potential
risks. Teriparatide should not be prescribed to PHARMACOECONOHIC CONSIDERATIONS
patients who are at increased baseline risk for Teriparatide is reserved for patients, both men and
osteosarcoma (including those with Paget's disease of postmenopausal women, who are at high risk for
bone or unexplained elevations of ALP; children; and fractures. No published pharmacoeconomic studies
young adults with open epiphyses or prior radiother- have compared the use of teriparatide with tradition-
apy of the skeleton). Patients with preexisting hyper- al agents used for the treatment of osteoporosis, such
calcemia, bone metastases, or a history of skeletal as bisphosphonates, estrogens, and calcitonin.
malignancies or metabolic bone disease other than The average wholesale cost of teriparatide is
osteoporosis should not use teriparatide. $20.81/d. Therefore, the estimated total 2-year cost of
teriparatide is >$15,000.11 Compared with other
DOSAGE AND ADHINISTRATION medications that are currently on the market for the
Teriparatide is supplied as a sterile, colorless, transpar- management of osteoporosis, teriparatide exceeds the
ent, isotonic solution in a glass cartridge that is pre- monthly amount a patient would pay compared with
assembled into a disposable pen for SC injection. 7 the other medication alternatives (Table). Teriparatide
Each pen is filled with 3.3 mk to deliver 3 mk of drug. 7 is calculated as costing 8-fold more a month than
Each milliliter contains teriparatide 250 tag (corrected other available medications (personal communication,
for acetate, chloride, and water content), glacial acetic Amerisource Bergen Distribution, March 29, 2004),
acid 0.41 rag, sodium acetate (anhydrous) 0.10 rag, which can be a growing concern for many patients
mannitol 45.4 rag, metacresol 3.0 rag, and water for who choose this as a treatment option.
injection. In addition, hydrochloric acid solution 10%
and/or sodium hydroxide solution 10% may have been
added to adjust the product to pH 4. Table. Cost of 30 days' treatment for osteoporosis.*
Teriparatide is indicated in postmenopausal
women with osteoporosis and men with primary or Drug Dosage Cost, $
hypogonadal osteoporosis who are at high risk for
Alendronate sodium I 0 mg PQ QD 69.00
fracture.1 The recommended dosage is 20 lag SC QD,
70 mg PQ Q W 65.00
injected into the thigh or abdominal wall, for 28 Risendronate sodium S mg PO QD 66.00
days. 7 Clinical trials of the higher dosage (40 lag SC 35 mg PO Q W 64.00
QD) 3,4,6-s have shown increased efficacy but de- Raloxifene hydrochloride 60 mg PO QD 71.00
creased tolerability Two trials 12,36showed that patients Calcitonin (salmon) 100 lU SC/II QD II 3.00
receiving 40 lag had more complaints of headache 200 lU intranasal QD 69.00
Teriparatide 20 IJg SC QD 624.18
(13% vs 8% in the placebo group) and nausea (18%
vs 8% in the placebo group) than those receiving 20 *Retail cost based on personal communication, Amerisource Bergen
lag, whereas the results for nausea and vomiting were Distribution, Narch 29, 2004
similar to placebo. Due to potential orthostatic effects
of teriparatide, initial doses should be administered
with the patient sitting or lying down if symptoms of CONCLUSIONS
orthostatic hypotension occur.1 The pen delivers the Teriparatide represents an important new advance in
recommended dose of 20 lag of teriparatide per day the therapy for osteoporosis. The exact role of ted-
The prescribing information 7 recommends discarding paratide in the management of osteoporosis still needs
the teriparatide pen after the 28-day usage period, to be defined. Tedparatide has a place in therapy as an
even if the pen contains unused solution. The pen alternative agent. Its efficacy and safety must be con-
should be stored in a refrigerator at 2°C to 8°C firmed. Investigators have found that hPTH (1-34) is
(36°F to 46°F) at all times. Patients should inject effective when used as a single agent or in combina-

852
 E. Quattrocchi and H. Kourlas

tion with alendronate to increase BMD. The NIH will mineral density in postmenopausal women with osteo-
determine whether the efficacy of combination treat- porosis. N Engl J Med. 2001 ;344:1434-1441.
ment with hPTH (1-34) plus a bisphosphonate is bet- 13. Zanchetta JR, Bogado CE, Ferretti JL, et al. Effects of
ter or worse than or no different from sequential the> teriparatide [recombinant human parathyroid hor-
ap> The combination of agents might be significantly mone (1-34)] on cortical bone in postmenopausal
more potent than either agent alone because antire- women with osteoporosis. J Bone Miner Res. 2003;18:
sorptive and anabolic agents work by completely dif- 539-543.
ferent mechanisms of action. 14. Cosman E Nieves J, Woelfert L, et al. Alendronate does
not block the anabolic effect of PTH in post-
REFERENCES menopausal osteoporotic women. J Bone Miner Res.
1. National Institutes of Health, Osteoporosis and Related 1998; 13:1031-1033.
Bone Diseases--National Resource Center. Osteoporo- 13. Lindsay R, Nieves J, Formica C, et al. Randomised
sis. Available at: www.nof.orglosteoporosislindex.htm. controlled study of effect of parathyroid hormone on
Accessed August 13, 2003. vertebral-bone mass and fracture incidence among
2. Crandall C. Osteoporosis. A two article symposium. postmenopausal women on oestrogen with osteoporo-
Postgrad Med. 2003; 114:21-32. sis. Lancet. 1997;350:550-555.
3. NIH Consensus Development Panel. Osteoporosis pre- 16. Roe EB, Sanchez SD, Del-Puerto GA, et al. Parathyroid
vention, diagnosis, and therapT~ ,lAMA. 2001;285:785- hormone 1-34 (hPTH 1-34) and estrogen produce dra-
793. matic bone density increases in postmenopausal osteo-
4. Steinweg KK. Osteoporosis. In: Rakel RE, ed. 5aunders porosis: Results from a placebo controlled randomized
Manual of Medical Practice. 2nd ed. Philadelphia, Pa: trial. J Bone Miner Res. 1999;14:5137.
WB Saunders; 2000:928-931. 17. Cosman E NievesJ, Woelfert L, et al. Parathyroid hor-
3. Rubin MR, Bilezikian JE New anabolic therapies in mone added to established hormone therapy: Effects
osteoporosis. Endocrinol Metab Clin North Am. 2003; on vertebral fracture and maintenance of bone mass
32:285-307. after parathyroid hormone withdrawal. J Bone Miner
6. Simonelli C. Parathyroid hormone: A new treatment Res. 2001;16:925-931.
option for osteoporosis. Pharmacy and Therapeutics. 18. Lane NE, Sanchez S, Modin GW, et al. Bone mass
2002;2-/:410-413. continues to increase at the hip after parathyroid hor-
7. Forteo (teriparatide [rDNA origin] injection) [package mone treatment is discontinued in glucocorticoid-
insert]. Product Information. Indianapolis, Ind: Eli induced osteoporosis: Results of a randomized con-
Lilly and Co; 2002. trolled clinical trial. J Bone Miner Res. 2000; 15:944-951.
8. Bringhurst FR, Demay MB, Kronenberg HM, et al. 19. Lane NE, Sanchez S, Modin GW, et al. Parathyroid hor-
Hormones and disorders of mineral metabolism. In: mone treatment can reverse corticosteroid-induced
Wilson JD. Williams Textbook of Endocrinology. 9th ed. osteoporosis. Results of a randomized controlled clini-
Philadelphia, Pa: WB Saunders; 1998:1155-1210. cal trial. J Clin Invest. 1998;102:1627-1633.
9. Tashjian AH Jr, Chabner BA. Commentary on clinical 20. Rehman Q, Lang TE Arnaud CD, et al. Daily treatment
safety of recombinant human parathyroid hormone with parathyroid hormone is associated with an
1-34 in the treatment of osteoporosis in men and post- increase in vertebral cross-sectional area in post-
menopausal women. J Bone Miner Res. 2002;1-/: 1131- menopausal women with glucocorticoid-induced
1161. osteoporosis. Osteoporosis Int. 2003; 14:77-81.
10. Rosen CJ, Bilezikian JE Clinical review 123: Anabolic 21. Crandell C. Review: Parathyroid hormone increases
therapy for osteoporosis. J Clin Endocrinol Metab. 2001; lumbar spine bone mineral density and decreases verte-
86:957-964. bral fractures in osteoporosis. ACP J Club. 2003;139:
11. Honeywell M, Phillips S, Branch E, et al. Teriparatide 11.
for osteoporosis: A clinical review. Pharmacy and 22. Rittmaster RS, Bolognese M, Ettinger ME et al.
Therapeutics. 2003;28:-/13-716. Enhancement of bone mass in osteoporotic women
12. Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of with parathyroid hormone followed by alendronate.
parathyroid hormone (1-34) on fractures and bone J Clin Endocrinol Metab. 2000;85:2129-2134.

833
CLINICAL THERAPEUTICS®

23. Brown SA, Rosen CJ. Osteoporosis. Meal Clin North Am. in Exp Clin Endocrinol Diabetes. 2002;110:100]. Exp Clin
2003;87:1039-1063. Endocrinol Diabetes. 2001;109:350-354.
24. Body JJ, Gaich GA, Scheele WH, et al. A randomized 30. Patel SR, Benjamin RS. Soft tissue and bone sarcomas
double-blind trial to compare the efficacy of teriparatide and bone metastases. In: Braunwald E, ed. Harrison's
[recombinant human parathyroid hormone (1-34)] with Principles of Internal Medicine. 15th ed. New York, NY:
alendronate in postmenopausal women with osteoporo- McGraw-Hill; 2001:625-628.
sis. J Clin Endocrinol Metab. 2002;87:4528-4535. 31. Arndt C, Crist WM. Common musculoskeletal tumors
23. Campion JM, Maricic MJ. Osteoporosis in men. Am of childhood and adolescence. N Engl J Meal. 1999;
Faro Physician. 2003;67:1321-1326. 341:342-352.
26. Kurland ES, Cosman F, McMahon DJ, et al. Parathyroid 32. White LM, Kandel R. Osteoid-producing tumors of
hormone as a therapy for idiopathic osteoporosis in bone. 5emin Musculoskelet Radiol. 2000;4:23-43.
men: Effects on bone mineral density and bone mark- 33. Benson CT, Voelker JR. Teriparatide has no effect on
ers. J Clin Endocrinol Metab. 2000;85:3069-3076. the calcium-mediated pharmacodynamics of digoxin.
27. Orwoll ES, Scheele WH, Paul S, et al. The effect of teri- Clin Pharmacol Ther. 2003;73:87-94.
paratide [human parathyroid hormone (1-34)] therapy 34. Hansen ME Nellissery MJ, Bhatia E Common mecha-
on bone density in men with osteoporosis. J Bone Miner nisms of osteosarcoma and Paget's disease. J Bone Miner
Res. 2003;18:9-17. Res. 1999;14(Suppl 2):39-44.
28. Levin RH. Pediatric and neonatal therapT~ In: Herfindal 33. Krane SM, Schiller AL. Paget's disease and other dys-
ET, Gourley DR, eds. Textbook of Therapeutics. Drug plasias of bone. In: Braunwald E, ed. Harrison's
and Disease Management. 7th ed. Philadelphia, Pa: Principles of Internal Medicine. 13th ed. New York, NY:
Lippincott Williams ¢r Wilkins; 2000:1955-1968. McGraw-Hill; 2001:2237-2243.
29. Koch CA. Rapid increase in bone mineral density in a 36. Deal C, Gideon J. Recombinant human PTH 1-34
child with osteoporosis and autoimmune hypopara- (Forteo): An anabolic drug for osteoporosis. Cleve Clin
thyroidism treated with PTH 1-34 [retraction appears J Meal. 2003;70:585-586, 589-590, 592-594.

Address correspondence to: Elaena Quattrocchi, PharmD, FASHE Pharmacy Practice Department, Arnold and
Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, 75 Dekalb Avenue, Brooklyn,
NY 11201-5497.

834