Title: PharmaNote
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Permanent Link: http://ufdc.ufl.edu/UF00087345/00033
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Title: PharmaNote
Series Title: PharmaNote
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Creator: University of Florida College of Pharmacy
Publisher: College of Pharmacy, University of Florida
Publication Date: August 2005
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Bibliographic ID: UF00087345
Volume ID: VID00033
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Janette Garcia, Pharm.D. Candidate

Osteoporosis is a global health concern that
results in significant morbidity and mortality and
increased healthcare costs. In the United States
(US) alone, it is estimated that 1.5 million people
experience osteoporotic related fractures with asso-
ciated costs of $14 billion each year.1'2 Of these
fractures, estimates indicate 700,000 vertebral frac-
tures, 250,000 hip fractures, 250,000 wrist frac-
tures, and 300,000 other limb fractures.3 Morbidity
associated with fractures can greatly interfere with
activities of daily living (ADL). After a vertebral
fracture, 80-90% of patients experience chronic
pain and 70% have difficulty completing ADL.4
One year after a hip fracture, up to 40% of women
are unable to walk independently and 60-80% are
unable to perform basic ADL.5 In spite of the large
number of affected individuals, 80% who have ex-
perienced at least one fracture, are neither identified
or treated.1'6 This is a testament to the fact that
there is a need to implement aggressive therapy for
the prevention and treatment of osteoporosis.
Osteoporosis results from an uncoupling of
osteoclastic and osteoblastic activity, with bone
loss occurring as a result of excess bone resorp-
tion.7 Osteoporosis is "characterized by low bone
mass and microarchitectural deterioration of bone

tissue leading to enhanced bone fragility and a con-
sequent increase in fracture risk."8 It can be clinically
categorized as: postmenopausal osteoporosis (PMO),
characterized mainly by vertebral and distal forearm
fractures; age-related osteoporosis, beginning shortly
after peak bone mass is obtained and affecting both
cortical and trabecular bone; or secondary osteoporo-
sis, caused by medications or diseases affecting both
types of bone.
Fractures represent the major complications
associated with osteoporosis. Since low bone mineral
density (BMD) is a major risk factor for fractures,
treatment for osteoporosis aims to prevent bone loss
or increase BMD in hopes of reducing the risk of
fractures.9 The World Health Organization (WHO)
classifies BMD based on t-scores, a comparison of
the patient's BMD with a reference population at
peak BMD.10 (Table 1) In the US, it is estimated that
54% of white postmenopausal women are osteopenic
and 30% are osteoporotic, and that by age 80, 27%
of women are osteopenic and 70% are osteoporotic.11
Furthermore, in any 10 year period white postmeno-
pausal women will experience 5.2 million fractures
of the hip, spine or distal forearm, resulting in over
$45 billion in direct medical expenditures.12 The de-
cision to treat warrants careful consideration of avail-
able therapeutic options and an assessment of the
patient's risk for fracture.9 Criteria have been estab-





Table 1. WHO definition of Osteoporosis,
t-score Classification
Above 1,0 Normal
-1 to ,5 steopenia or low BMD
Below 2,5 Osteoporosis
Below 2,5 plus fractures Severe osteoporosis
T t-score is the patients BMD compared with the mean BMD of a reference
population at peak BMD (age 25 years). Data adapted from [10]

lished that endorse initiating treatment in the follow-
ing patient groups: t-score below -1.5 plus additional
risk factors for fracture, t-score below -2.0, and age
above 70 years plus additional risk factors.8
Currently available therapies for the preven-
tion and treatment of PMO include: calcium and vi-
tamin D, hormone replacement therapy (HRT), se-
lective estrogen receptor modulators (SERMS) and
other estrogen analogues, bisphosphonates, calci-
tonin, and parathyroid hormone (PTH).9 The use of
calcium and vitamin D is insufficient for the treat-
ment of osteoporosis, but must accompany all phar-
macologic therapies. Although there are no current
recommendations as to which class of agents should
be the first-line choice, bisphosphonates have
emerged as an important treatment option. There are
currently three FDA-approved bisphosphonates for
the prevention and treatment of PMO.14 (Table 2)
The management of osteoporosis requires
lifelong adherence to interventions to reduce the risk
of fractures. It is important that adequate intake of
calcium and vitamin D be maintained by patients re-
ceiving bisphosphonate therapy. The National Osteo-
porosis Foundation (NOF) suggests a daily dietary
calcium intake of at least 1200 mg and vitamin D
400-800 IU/day for individuals at risk.13 Alendronate
and risedronate have been shown to reduce vertebral
and non-vertebral fracture risk and have been associ-
ated with increased BMD.14 In addition to the once-
daily formulations, both are available in a once-
weekly formulation. Analyses of prescription data
suggests that adherence is better to once-weekly dos-
ing regimens when compared to once-daily, however
the overall persistence and adherence to therapy at
one year still remains suboptimal, perhaps due to the
cumbersome dosing requirements with this class of
Roche Pharmaceuticals in conjunction with
GlaxoSmithKline announced on March 25, 2005 the
approval of their supplemental new drug application

(sNDA) for ibandronate (Boniva) 150 mg tablets.
Ibandronate 150 mg is the first and only once-
monthly oral medication for the treatment and pre-
vention of PMO.17 Although ibandronate was previ-
ously approved as a once-daily dosage regimen, it
was never marketed in the US. The new once-month
ly dosage form was made available by prescription in
US pharmacies in April 2005. Once-monthly iban-
dronate provides patients with another option for os-
teoporosis prevention and treatment that may in-
crease adherence. This article will examine the role
of once-monthly ibandronate for the prevention and
treatment of postmenopausal osteoporosis.

Pharmacology and Pharmacokinetics
Ibandronate's mechanism of action (MOA) is
in part mediated by its binding to hydroxyapatite
which is part of the mineral matrix of bone. Ibandro-
nate's chemical structure confers enhanced binding
to hydroxyapatite and increased affinity for calcium
in bone.14 The antiresorptive effects of ibandronate
result from actions on osteoclast activity including:
inhibition of osteoclast recruitment and activity on
the bone surface, induction of osteoclast apoptosis,
and alterations in bone mineral that reduce the rate of
dissolution.14'18 Ibandronate produces measurable
biochemical changes indicative of decreased bone
resorption, such as decreases in deoxypyridinoline
and cross-linked C-telopeptide of Type I collagen.18
Ibandronate's mean peak plasma concentra-
tion is achieved within 0.5 to 2.0 hours after oral ad-
ministration when fasting. Absorption takes place in
the upper gastrointestinal (GI) tract and is impaired
by food or beverages other than water. Oral bioavail-
ability of ibandronate 2.5 mg is approximately 0.6%
compared to intravenous dosing, and is reduced by as
much as 90% when it is taken with a meal. Following
absorption, ibandronate is rapidly bound to bone or
excreted in the urine. Ibandronate has a volume of
distribution (Vd) of at least 90 L with 40% to 50% of
the circulating dose binding to bone. There is no evi-
dence that ibandronate is metabolized, and the por-
tion not removed from circulation by bone uptake is
eliminated unchanged by the kidneys. Ibandronate
not absorbed by the gut is eliminated unchanged in
the feces. Ibandronate exhibits multiphasic elimina-
tion, with a slower clearance phase as it redistributes
back into circulation from bone. The observed termi-
nal half-life in healthy post-menopausal women who
received ibandronate 150 mg varied between 37 to

Table 2. FDA approved bisphosphonates for the treatment of postmenopausal osteoporosis.14

Drug Name Once-daily dose Once-weekly dose Once-monthly dose

Alendronate (Fosamax") 10 mg every day 70 mg every week

Risedronate (Actonel") 5 mg every day 35 mg every week

Ibandronate (Boniva') 2.5 mg every dayt 150 mg every months
Not marketed in the US, lApproved on March 24, 2005.

157 hours, and was found to be dependent on the
dose and assay sensitivity. Ibandronate exerts favor-
able effects on bone turnover months to years fol-
lowing discontinuation of therapy due to its high af-
finity for hydroxyapatite and slow redistribution
from bone to plasma. 18
Due to its exclusive renal elimination, the
clearance of ibandronate is decreased with impaired
renal function. In patients given ibandronate 0.5 mg
intravenously, those with a creatinine clearance
(CrCL) of 40 to 70 mL/min had a 55% higher area
under the curve (AUC) than those patients with a
CrCL >90 mL/min. Patients with a CrCL <30 mL/
min had more than a two-fold increase in exposure.
No gender differences were identified in bioavail-
ability and pharmacokinetics of ibandronate, and any
pharmacokinetic differences due to race have not
been studied. 18

Clinical Trials
Treatment ofPostmenopausal Osteoporosis
The oral ibandronate osteoporosis vertebral
fracture trial in North America and Europe (BONE)
was a 3-year, multinational, randomized, double-
blind, placebo-controlled study that evaluated the
efficacy and safety of ibandronate for the treatment
of PMO in 2946 women.19 Patients were randomized
to receive ibandronate 2.5 mg every day, ibandronate
20 mg intermittently (20 mg every other day x 12
doses every 3 months), or placebo. All patients re-
ceived 400 IU vitamin D and 500 mg calcium at bed-
time. Patient baseline demographic characteristics
were comparable among the three treatment groups.
Inclusion criteria were: 55-80 years of age, at least 5
years post-menopausal, lumbar spine BMD t-scores
between -2.0 and -5.0 in at least one vertebra (Ll-
L4), and 1 to 4 baseline vertebral fractures. The pri-
mary endpoint measured in this intention-to-treat
trial was the incidence of new vertebral fractures.
The secondary endpoints included: incidence of new

or worsening vertebral fractures, clinical vertebral
fractures, clinical osteoporotic nonvertebral frac-
tures, relative change in BMD and bone turnover
markers, and change in height.18,19
At 3 years, both ibandronate treatment groups
produced statistically significant decreases in the in-
cidence of new vertebral fractures and new or wors-
ening vertebral fractures compared with placebo.
(Table 3) There was no difference in the antifracture
efficacy between the two ibandronate treatment
groups. No statistically significant difference was
observed in the incidence of nonvertebral fractures
across the three treatment groups (Table 3). How-
ever, a post-hoc analysis of patients at higher risk for
nonvertebral fractures (defined as a baseline femoral
neck BMD t-score < -3.0) revealed that treatment
with ibandronate 2.5 mg every day resulted in a sta-
tistically significant reduction in the incidence of
nonvertebral fractures (relative risk reduction [RRR]
69%, p=0.01) at 3 years. The intermittent ibandro-
nate treatment group did not achieve a statistically
significant reduction in nonvertebral fractures (RRR
37%, p=0.22). Patients in both ibandronate treatment
groups had statistically significant increases in BMD
at the lumbar spine and hip relative to baseline and
compared to placebo. The increase in BMD was sta-
tistically significant by 6 months, and was progres-
sive over the 3-year treatment period. The treatment
groups also demonstrated statistically significant re-
ductions in markers of bone turnover and height loss
compared with the placebo group. The newly formed
bone during treatment was found to have normal
composition and quality, with no indication of osteo-
malacia or mineralization defects. Treatment with
ibandronate was well tolerated and demonstrated a
broad margin of safety with an adverse event profile
similar to that of placebo.19
The monthly oral ibandronate in ladies study
(MOBILE) is a 2-year, multinational, randomized,
double-blind, non-inferiority study undertaken with

Table 3. Incidence of fractures reported in the BONE Trial.19
Placebo Ibandronate 2.5 mg daily [RRR] Ibandronate 20 mg (intermittent)*
(n=975) (n=977) [RRR] (n=977)
1st new vertebral fracture 9.6% 4.7% [52%]t 4.9% [50%]t
1st new or worsening fracture 10.4% 5.1% [52%] 5.8% [46%]
Clinical vertebral fracture 5.3% 2.8% [49%]T 2.8% [48%]0
Clinical fractures 13.0% 11.6% 11.2%
Nonvertebral fractures 8.2% 9.1% 8.9%

RRR= Relative risk reduction versus placebo. *Intermittent dosing= 20 mg every other day x 12 doses every 3 months. Statistical significance p<0.0005, Statistical
significance p<0.015. Data adapted from reference 19.

the purpose of comparing the safety and efficacy of
monthly versus daily ibandronate dosing in the
treatment of PMO. The study is currently in its sec-
ond year, but one-year data for primary and secon-
dary endpoints has been published.20 The 1609
women enrolled met the following criteria: 55-80
years of age, 5 or more years postmenopausal, and
a lumbar spine t-score between -2.5 and -5.0. The
patients were randomized to receive: 50/50 mg
monthly (50 mg doses on 2 consecutive days), 100
mg every month, 150 mg every month, or 2.5 mg
every day. Since the antifracture efficacy and safety
of ibandronate 2.5 mg every day was previously
established, this dosing schedule was used as the
reference arm.19 All patients received 400 IU vita-
min D and 500 mg calcium. Patient baseline demo-
graphic characteristics were comparable across all
treatment arms. The primary endpoint is the rela-
tive change from baseline in lumbar spine BMD
[L2-L4]. Secondary endpoints include the relative
change in BMD of the total hip, femoral neck, and
trochanter, as well as changes in serum C-
telopeptide (sCTX) and a retrospective analysis of
bone-specific alkaline phosphatase (BSAP).20
The 1-year analysis demonstrated that
monthly ibandronate produced increases in lumbar
spine BMD of at least equal magnitude to that pro-
duced by ibandronate daily (Table 4). Tests for su-
periority found ibandronate 150 mg once-monthly
to be superior to the once-daily regimen with re-
gard to the primary endpoint (p=0.002). The iban-
dronate monthly regimen was comparable to the
once-daily regimen for increases in BMD at all hip
sites. The once-monthly ibandronate regimens pro-
duced decreases in markers of bone turnover sCTX
and BSAP. A responder analysis was done to deter-
mine if patients were achieving increases in BMD

that correlate with antifracture efficacy (BMD in-
creases >6% at lumbar spine, or >3% at hip). This
analysis showed that when compared to the once-
daily regimen, significantly more patients receiving
ibandronate 100 mg or 150 mg monthly achieved the
aforementioned increases in BMD. Furthermore, a
safety analysis showed that monthly ibandronate is
well tolerated and has a safety profile similar to that
of daily ibandronate.20

Prevention ofPostmenopausal Osteoporosis
A randomized, double-blind, placebo-
controlled 2-year study of 654 postmenopausal
women without osteoporosis at baseline, demon-
strated the efficacy of ibandronate 2.5 mg every day
for the prevention of bone loss. Inclusion criteria
were: women aged 41 to 82 years, average of 8.5
years postmenopausal, lumbar spine BMD t-scores >
-2.5. Patients were stratified according to years after
menopause (1 to 3 years, >3 years) and baseline lum-
bar spine BMD (t-scores: >-1, -1 to -2.5). The study
compared ibandronate 0.5 mg, 1.0 mg, or 2.5 mg
every day with placebo. All patients received 500 mg
of calcium once daily. The primary efficacy measure
was a change in lumbar spine BMD at the end of
study period. Ibandronate 2.5 mg every day resulted
in a mean increase in lumbar spine BMD of 3.1%
over placebo. Lumbar spine BMD increases were
seen at 6 months and at all later time points when
comparing ibandronate 2.5 mg every day to placebo
across all four baseline strata. Currently the safety
and efficacy of ibandronate 150 mg monthly for the
prevention of PMO is being studied.18

Dosing and Administration
The ibandronate once-monthly formulation is
available as a 150 mg film-coated tablet. Ibandronate

Table 4. Mean change from baseline in lumbar spine
BMD in the MOBILE Trial.20
50/50 100 150
Ibandro- 2.5 mg/d mg/mo. mg/mo. mg/mo.
nate (n=318) (n=330) (n=315) (n=327)
vs. Base- 3.9 4.3 4.1 4.91
line (%)
Tp=0.002 for comparison versus 2.5 mg/daily.

150 mg tablets should be taken on the same day of
each month (i.e., January 15, February 15, etc.). If a
patient misses a dose it should be taken on the morn-
ing following the date it is remembered. The patient
should then continue taking ibandronate according to
their original schedule. A patient should not take
two 150 mg tablets within the same week. If the
missed dose is remembered 1 to 7 days before the
next scheduled dose, the patient should skip the
missed dose and take the next scheduled dose con-
tinuing on their original schedule. 18
Ibandronate should be taken in the morning,
at least 60 minutes before the first food or drink
(other than water) of the day, and before taking any
oral medications containing multivalent cations. To
reduce the risk of esophageal irritation, tablets
should be swallowed whole with a full glass of plain
water while the patient is standing or sitting. The
patient should then remain upright for 60 minutes
after taking ibandronate.18
Drug interactions have been identified with
products containing calcium and other multivalent
cations since they are likely to interfere with the ab-
sorption of ibandronate. Like other bisphosphonates,
ibandronate does not interfere with cytochrome
P450 (CYP450) activity and does not influence the
elimination of drugs dependent upon this route of
elimination. No drug interaction or increased inci-
dence of adverse effects was reported in patients
treated with concomitant aspirin or nonsteroidal anti-
inflammatory drugs (NSAIDs).18 However, on the
basis of potential additive gastrointestinal mucosal
toxicity and post marketing reports with other
bisphosphonates, caution is warranted when these
agents are used together.1

Toxicity and Safety
Results from clinical trials comparing treat-
ment with daily ibandronate versus placebo, demon-
strated an overall adverse event profile similar to
that of placebo.18,19 Results from the MOBILE study
found that ibandronate 150 mg monthly was gener-

Table 5. Monthly retail cost of bisphosphonate therapy.
Drug Cost ($/month)
Alendronate (Fosamax") $ 76.90
Ibandronate (Boniva') $ 80.37
Risedronate (Actonel") $ 75.95
Average retail cost from 3 community pharmacies in Gainesville, FL 32601.

ally well-tolerated and has a safety profile similar
to that of daily ibandronate.20 The most commonly
reported adverse events included hypertension, dys-
pepsia, arthralgia, back pain, nausea, and diarrhea.
Upper GI events were rare in the four treatment
arms of the MOBILE study and no differences
were observed among treatment groups. The most
common complaints were dyspepsia, nausea, and
abdominal pain. Overall, the incidence of GI ad-
verse events was higher in patients taking NSAIDs
and those with a history of GI disorders, however
there were no differences in the incidence of ad-
verse events across the four treatment arms. The
incidence of influenza-like illness was higher in the
monthly treatment groups (6.6%-8.3%) compared
with the daily group (2.8%). However, the majority
of adverse events occurring after the first dose,
were short in duration, and resolved without treat-
Contraindications to the use of ibandronate
include: known hypersensitivity to ibandronate or
to any of its excipients, uncorrected hypocalcemia,
or an inability to stand or sit upright for at least 60
minutes. Ibandronate is not recommended for use
by patients with severe renal impairment defined as
a CrCL <30 mL/min.18

As of April 2005, Boniva was made avail-
able by prescription in US pharmacies. It comes
packaged as a 3-month supply (3 tablets). Table 5
lists the average retail cost for Boniva compared
to the cost of the other bisphosphonates.

Ibandronate (Boniva) 150 mg is the first
once-monthly oral medication for the treatment of
any chronic disease. Ibandronate is indicated for
the prevention and treatment of postmenopausal
osteoporosis. Ibandronate is effective in treating
postmenopausal osteoporosis by increasing bone
mass density and decreasing the risk of vertebral

fractures. Newly formed bone is of normal quality
and has no indication of osteomalacia or mineraliza-
tion defects. Ibandronate decreases nonvertebral
fractures in a subgroup of postmenopausal women at
higher risk for fractures (femoral neck t-scores <-
The main benefit of ibandronate over other
available bisphosphonates may be the more conven-
ient dosing regimen. As a once-monthly drug, iban-
dronate is an alternative for patients struggling with
the administration of bisphosphonates either daily or
weekly. The once-monthly regimen may help in-
crease adherence to drug therapy. Further studies are
needed to determine the full benefits of ibandronate
on nonvertebral fractures. Head-to-head trials with
available bisphosphonates are warranted to better
establish the role of ibandronate for postmenopausal

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New Drug Approvals

Ramelteon (RozeremTM, Takeda
Pharmaceuticals), the first melatonin receptor
agonist, is approved for the treatment of
acute or chronic insomnia. Unique among
agents used to treat insomnia, RozeremTM is
not a controlled substance. The approved
dose is one 8 mg tablet 30 minutes before
bedtime. It should not be prescribed to
patients with severe hepatic impairment or
those receiving fluvoxamine.

The PharmaNote is Published by:
The Department of Pharmacy
Services, UF Family Practice Medical
Group, Departments of Community
Health and Family Medicine and
Pharmacy Practice
University of Florida

John G. Gums Editor

R. Whit Curry, M.D. Associate Editor

Benjamin J. Epstein Assistant Editor

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