Title: PharmaNote
ALL VOLUMES CITATION PDF VIEWER THUMBNAILS PAGE IMAGE ZOOMABLE
Full Citation
STANDARD VIEW MARC VIEW
Permanent Link: http://ufdc.ufl.edu/UF00087345/00072
 Material Information
Title: PharmaNote
Series Title: PharmaNote
Physical Description: Serial
Language: English
Creator: College of Pharmacy, University of Florida
Publisher: College of Pharmacy
Place of Publication: Gainesville, Fla.
Publication Date: March 2009
 Record Information
Bibliographic ID: UF00087345
Volume ID: VID00072
Source Institution: University of Florida
Holding Location: University of Florida
Rights Management: All rights reserved by the source institution and holding location.

Downloads

This item has the following downloads:

March2009 ( PDF )


Full Text
















ZOLEDRONIC ACID:
ONCE-YEARLY TREATMENT
FOR OSTEOPOROSIS

Nancy King, Pharm.D. Candidate




Osteoporosis is a skeletal disorder character-
ized by low bone mass and structural deterio-
ration of bone tissue leading to bone fragility
and an increased susceptibility to fractures, particu-
larly of the hip, spine and wrist. It occurs in an esti-
mated 44 million Americans, accounting for 55% of
the people 50 years of age and older.1 By the year
2020, 1 in 2 Americans is expected to either have or
be at risk of developing osteoporosis.2 Without ap-
propriate therapy, annual hip fractures are estimated
to increase from 300,000 to 6.2 million in the year
2050.3
A common evaluation marker in the diagnosis
and evaluation of osteoporosis is the T-score meas-
urement of the bone mineral density (BMD) derived
from dual energy X-ray absorptiometry (DEXA) of
the hip or spine.3 T-score is a classification of BMD
according to the standard deviation (SD) difference
between a patient's BMD and that of a young-adult
reference population established by the World Health
Organization (WHO) in 1994. A normal T-score is -
1.0 or higher, low bone mass (osteopenia) between -
1.0 and -2.5, and osteoporosis as equal to or less than
-2.5.4,5 Additionally, excessive bone resorption by
osteoclasts leads to decreased bone mass and bone
strength. This resorption activity can be quantified
by the presence of serum (alkaline phosphatase/ALP,


C- and N-terminal propeptides of type 1 collagen)
and urine (C- and N-telopeptides of type 1 collagen
or CTx and NTx) biochemical markers. These mark-
ers reflect bone remodeling but do not indicate cur-
rent BMD; therefore, do not replace DEXA for os-
teoporosis diagnosis.3
Bisphosphonates are the mainstay of therapy for
osteoporosis.6 Alendronate (Fosamax), risendronate
(Actonel) and ibandronate (Boniva) are the oral
bisphosphonates indicated for prevention and treat-
ment of osteopososis; whereas, ibandronate
(Boniva) and zoledronic acid (Reclast) are the in-
travenous (IV) bisphosphonates for treatment of os-
teoporosis.8 Oral bisphosphonates have poor intesti-
nal absorption and can cause gastrointestinal intoler-
ance, heartburn, esophageal irritation and esophagi-
tis, which often reduce adherence.9 At the end of one
year of bisphosphonate therapy, approximately one-
third of patients taking Qdaily dosing and less than
one-half of those taking Qweekly dosing continued
their therapy.315 Zoledronic acid (Reclast) is the
first FDA-approved bisphosphonate for once-yearly
IV treatment of postmenopausal osteoporosis. It is
also approved for treatment of Paget's disease and
recently, for treatment of osteoporosis in men.14 Zo-
meta is another IV formulation of zoledronic acid
indicated for treatment of hypercalcemia of malig-




INSIDE THIS ISSUE:
ZOLEDRONIC ACID: ONCE-YEARLY
TREATMENT FOR OSTEOPOROSIS



,i ^ ^ ^ -^ ^ ^ ^ r ,


mm


PharmaNote


VOLUME 24, ISSUE 6 MARCH 2009
i ^ ^ ^ ^^ ^ ^ ^ ^ ^^ ^ ^ ^ ^^ ^ ^ ^i^^ ^ ^ ^ j


Volume 24, Issue 6 1 March 2009


PharmaNote







nancy, multiple myeloma and bone metastasis from
solid tumors.16 This article will review the safety,
efficacy and tolerability of zoledronic acid
(Reclast) as an option in the management of osteo-
porosis.


PHARMACOLOGY AND PHARMACOKINETICS

Zoledronic acid is an inhibitor of osteoclast-
mediated bone resorption. It has high binding affinity
to bone mineral hence its long duration of action.
Zoledronic acid rapidly partitions to bones and local-
izes preferentially at sites of high bone turnover. The
enzyme farnesyl pyrophosphate synthase is its main
molecular target in the osteoclast.14
No in vivo drug interaction studies have been
performed for zoledronic acid. The drug has low af-
finity for blood components and has moderate pro-
tein binding capacity in human plasma. It is not me-
tabolized and is excreted into the urine as the intact
drug. Zoledronic acid clearance is independent of
dose but dependent on creatinine clearance. No dos-
age adjustment is required in patients with creatinine
clearance (CLcr) of 3 35 mL/min but is not recom-
mended for patients with severe renal impairment
(CLcr <35 mL/min).14


CLINICAL TRIALS

Dose-Ranging Efficacy and Long-Term Safety
A multinational, one-year, phase 2 study by Reid
et al randomized 351 postmenopausal women aged
45-80 years to receive either placebo (n=59) or intra-
venous zoledronic acid in doses of 0.25 mg (n=60),
0.5 mg (n=58), or 1 mg (n=53) at three-month inter-
vals; a total annual dose of 4 mg as a single dose
(n=60); or two doses of 2 mg administered six


months apart (n=61).17 The primary endpoint was the
lumbar-spine BMD. At the end of the study, no sig-
nificant differences among the zoledronic acid
groups were observed. All zoledronic acid treatment
groups had 4.3- 5.1% lumbar spine BMD higher than
the placebo group (p<0.001) and 3.1-3.5% femoral
neck BMD higher than placebo group (p<0.001).
There was a significant decrease in serum CTx of 49-
52% with zoledronic acid vs. 8% decrease with pla-
cebo (p<0.01).14 Treatment-related dropout rates
were similar to that in the placebo group although
myalgia and pyrexia occurred more commonly in the
zoledronic acid groups. Based on the active treat-
ment groups' increase in BMD, decrease in serum
bone turnover markers and low incidence of adverse
events, the investigators concluded that an annual
infusion of zoledronic acid might be an effective
treatment for postmenopausal osteoporosis.14
Devogelaer and colleagues investigated the effi-
cacy and safety of zoledronic acid 4 mg over 5 years
in postmenopausal osteoporosis.18 This investigation
was composed of the previous 1-year study by Reid
et al117 followed by two consecutive, 2-year, open-
label extension studies. A total of 119 women com-
pleted the core study and were randomized to receive
yearly doses of placebo (n=19), four 0.25-mg zole-
dronic acid doses (n=20), four 0.5-mg zoledronic
acid doses (n=19), four 1-mg zoledronic acid doses
(n=19), two 2-mg zoledronic acid doses (n=22), or
one 4-mg zoledronic acid dose (n=20). Most study
participants in the first extension study received an-
nual zoledronic acid 1 mg every 3 months (n=105)
while others received 0.5 mg every 3 months
(n=14).3'18 Patients who entered the second extension
received either 4 mg per year of zoledronic acid
(n=22) or calcium only (n=97) and were divided into
three subgroups according to years of active treat-
ment received (2 years, n=19; 3 years, n=78; or


Table 1: Zoledronic Acid vs. Placebo in the HORIZON Pivotal Fracture Trial19'25

OUTCOME MEASUREMENT ZOLEDRONIC ACID PLACEBO RRR (95% CI) NNT (95% CI)

Vertebral fracture (stratum I) 3.3% 11% 70% (62-76) 14 (13-15)
Hip fracture 1.4% 2.5% 41% (17-58) 98 (69-236)
Nonvertebral fracture 8.0% 11% 25% (13-36) 38 (26-72)
Any clinical fracture 8.4% 13% 33% (23-42) 24 (19-34)
RRR = relative risk reduction; NNT = number needed to treat

r i ii ai 1i A v IIIa- t ,^ I .IIA. & I .A 6Ar fnnJ


W U1110 QQUQ C1 I%,~ilLVV


llrI lma0 tiLe







Table 2: Adverse Events of the HORIZON Pivotal Fracture Trial
ZOLEDRONIC ACID PLACEBO
EVENT P VALUE
(N=3862) (N=3852)
Any adverse event, n (%) 3688 (95.5) 3616 (93.9) 0.002
Any serious adverse event 1126 (29.2) 1158 (30.1) 0.4
Death 130(3.4) 112(2.9) 0.27
Discontinuation of follow-up due to adverse event 80(2.1) 70(1.8) 0.41
Five most common post-dose symptoms (<3 days after infusion)
Pyrexia 621(16.1) 79(2.1) <0.001
Myalgia 365 (9.5) 66 (1.7) <0.001
Influenza-like symptoms 301(7.8) 61(1.6) <0.001
Headache 273 (7.1) 90 (2.3) <0.001
Arthralgia 245 (6.3) 76 (2.0) <0.001
Any of the five most common post-dose symptoms
After first infusion 1221 (31.6) 237 (6.2) <0.001
After second infusion 253 (6.6) 79 (2.1) <0.001
After third infusion 108 (2.8) 42 (1.1) <0.001
Atrial fibrillation
Any event 94 (2.4) 73 (1.9) 0.12
Serious adverse event 50 (1.3) 20 (0.5) <0.001
Stroke
Serious adverse event 87 (2.3) 88 (2.3) 0.94
Death from stroke 20 (0.5) 11(0.3) 0.15



5 years, n=22). Changes in BMD measured by treatment regimens, open-label design, and lack of
DEXA and bone turnover markers (bone ALP and randomization in both of the extension studies.
CTx) were assessed. All subgroups showed substan-
tial increases in BMD of lumbar spine (6.4-9%), Fracture Risk Studies
proximal femur (4.9-5.5%), distal radius (2.2-3%), The 3-year international, multicenter, randomized
and total body (3.6-5%) by the end of the study. placebo-controlled Health Outcomes and Reduced
There was no sustained reduction in bone turnover in Incidence with Zoledronic Acid Once Yearly
any of the treatment groups based on increases in (HORIZON) Pivotal Fracture Trial by Black et al
ALP and CTx levels from month 24 in participants was the first study to evaluate fracture risk with zole-
treated for 5 years. The most frequent adverse events dronic acid use.19 The trial included 7,736 women
were arthralgia, hypertension, back pain, naso- aged 65-89 (mean age = 73), who had BMD T-score
pharyngitis, osteoarthritis, falls, bronchitis and pain of -2.5 or less at the femoral neck, with or without
in an extremity. A total of 8 patients (6.7%) experi- evidence of existing vertebral fracture; or a T-score
enced serious adverse events, with 7 of the 15 total of -1.5 or less, with at least two mild or one moder-
events reported as cardiovascular-related. Six pa- ate existing vertebral fracture. Study participants
tients reported a fracture during the study. Devoge- were placed into one of two strata based on their use
laer et al18 concluded that zoledronic acid 4 mg once- of osteoporosis medications at baseline. Stratum I
yearly increased BMD and decreased bone resorp- included patients with no concomitant use of osteo-
tion although this drug regimen may not be sufficient porosis therapy (n=6,113); stratum II included those
in reducing bone remodeling activity. Limitations of with baseline concomitant use of anti-osteoporosis
the study included small treatment groups, multiple therapy excluding bisphosphonates (n=1,652). The


- i i 1 -IuII Ir J M I -- 6 A -nnJ


W U1110 QQUQ C11%,l~ilLVV


0ri l olte0 iWL






investigators believed that permitting the use of non-
bisphosphonate therapies would not have an impor-
tant influence on the overall outcome as only alen-
dronate and risedronate had nonvertebral fracture
risk reduction data at the time of study.20 Patients
were randomly assigned to a single dose of 5 mg
zoledronic acid infused over 15 minutes (n=3,889) or
placebo (n=3,876) once a year for three consecutive
years. Both groups received calcium and vitamin D
supplementation. New vertebral fractures in stratum
1 and hip fracture in both strata were the primary
endpoints of the trial.
During the 3-year period, the active treatment
group had a 70% relative risk reduction of mor-
phometric vertebral fracture as compared with pla-
cebo (p<0.001) and 41% relative risk reduction of
hip fracture (p=0.002). The reduction for nonverte-
bral fractures, clinical fractures, and clinical verte-
bral fractures were 25%, 33%, and 77%, respectively
(all comparisons, p<0.001). Results for fracture risk
reduction are summarized in Table 1.
BMD scores at the total hip, lumbar spine and
femoral neck were significantly increased by 6.02%,
6.71% and 5.06%, respectively. The effect of zole-
dronic acid on biochemical markers was similar to
that reported for oral bisphosphanates. Bone remod-
eling levels after the infusions were also similar, sup-
porting the view that the 3-year annual infusion of
zoledronic acid improves bone strength without ad-
versely affecting remodeling capacity. Adverse
events were similar in two groups with pyrexia and
myalgia being most commonly reported (Table 2).
Serious atrial fibrillation, however, occurred more
frequently in the zoledronic acid group (50 vs. 20
patients, p <0.001). The authors concluded that a
once-yearly infusion of zoledronic acid significantly
reduced the risks for vertebral, hip and other frac-
tures.
Lyles and colleagues evaluated the safety and
efficacy of zoledronic acid for the prevention of new
clinical fracture in patients who had (<90 days of en-
rollment) undergone recent surgical repair of a hip
fracture and were unable or unwilling to take an oral
bisphosphonate.21 The HORIZON Recurrent Frac-
ture Trial was an international, multi-center, random-
ized, double-blind, placebo-controlled study involv-
ing men and women 50-95 years (mean age = 74.5),
randomly assigned to receive either zoledronic acid
(n=1,065) or placebo (n=1,062). Patients in the two
groups received supplemental vitamin D and cal-


cium. The median follow-up was 1.9 years. The
study continued until at least 211 patients in the
study population had confirmed clinical fractures.
Zoledronic acid significantly reduced the incidence
of any clinical fracture by 35%. The rates of any new
clinical fracture were 8.6% in the active treatment
group and 13.9% in the placebo group (p=0.001). In
the safety analysis, 101 of 1,054 patients died in the
zoledronic acid group (9.6%) vs. 141 of 1,057 pa-
tients in the placebo group (13.3%). This was a 28%
reduction in deaths from any cause in the zoledronic
acid group (p=0.01). Pyrexia, myalgia and bone and
musculoskeletal pain were the most frequent adverse
events reported. The rates for renal and cardiovascu-
lar adverse events, including atrial fibrillation and
stroke, were comparable between study groups. The
investigators concluded that once-yearly infusion of
zoledronic acid within 90 days after low-trauma hip
fracture repair was associated with new clinical frac-
ture rate reduction and improved survival.14'21

Comparative Studies for Osteoporosis
Saag and colleagues evaluated the onset of action
of single infusion zoledronic acid compared with
weekly oral alendronate by comparing relative
change from baseline in the bone resorption marker
urine NTx at week 1.22 The 24-week multicenter,
randomized, double-blind, double-dummy trial, in-
cluded postmenopausal women aged 45-70 years.
Study participants were assigned to receive weekly
alendronate 70 mg (n=59) or a single dose of zolen-
dronic acid 5 mg (n=69). Both groups were supple-
mented with calcium and vitamin D. At week 1,
zoledronic acid resulted in a significantly greater re-
duction in mean urine NTx from baseline than alen-
dronate 70 mg (p<0.0001). The reported adverse
events were comparable between study groups
(zoledronic acid 91.3%, alendronate 86.4%). Tran-
sient, flu-like symptoms were the most common ad-
verse events in the zoledronic acid group (18.8% vs.
5.1%). The majority of patients, including those who
experienced flu-like symptoms, preferred the annual
IV therapy (66.4%) compared to weekly oral therapy
(19.7%).
A 12-month noninferiority trial involving zole-
dronic acid and alendronate was conducted by
McClung et al.23 The study involved postmenopausal
women aged 45-79 years, with lumbar spine or
femoral neck BMD T-score values of <-2.0 who had
previously taken alendronate for at least one year


Phraoe oue2, su Mrh20


Volume 24, Issue 6 1 March 2009


PharmaNote







Table 3: Summary of Zoledronic Acid Clinical Trials

STUDY DESIGN DOSE RESULTS


Reid, et al.
(2002)1


. 3-y, double-blind, placebo-controlled
trial
. 7,765 postmenopausal women
. Primary end points: new vertebral frac-
ture (pts not taking concomitant osteo-
porosis medications) and hip fracture
(all pts)

. Randomized, double-blind, PCB-
controlled trial
. Median follow-up = 1.9 years
. Primary end point: new clinical fracture


. 24-week randomized, double-blind,
double-dummy trial
. Primary endpoints: reductions in urine
NTx at week 1, patients' preference of
weekly vs. yearly treatment

. 1-y double-blind, double-dummy trial
. Included postmenopausal women re-
ceiving oral alendronate for 1 year
immediately prior to randomization
. Primary endpoints: change in lumbar
spine BMD, relative change in bone
biomarkers




. 2-year randomized, doubleblind, active
controlled study
. 302 men aged 25-86 years (mean = 64)


. 1-y randomized, double-blind, PCB-
controlled trial
. 45-80 y.o. postmenopausal women
(n=351)
. Primary endpoint: lumbar-spine BMD




. 5-y study; 1-y core study;17 2 consecu-
tive 2-y, open-label extension studies
. 1st extension: majority receive 4 mg/yr
. 2nd extension: 4 mg/yr or calcium only
. Patients divided into three subgroups
according to years of active treatment
received (2, 3 or 5 years)
. Primary endpoints: Changes in BMD
and bone turnover markers


Devogelaer, et al.
(2007)18


. PCB (n=59)
. 5 ZA groups:
3 mo intervals: 0.25 mg (n=60),
0.5 mg (n=58), 1 mg (n=53)
single 4 mg dose (n=60)
2 doses: 2 mg, 6 mo interval
(n=61)

. PCB (n=19)
. ZA groups- annual dose:
4 doses 0.25 mg (n=20)
4 doses 0.5 mg (n=19)
4 doses 1 mg (n=19)
2 doses 2 mg (n=22)
1 dose 4 mg (n=20)
. 1st extension study: ZA 1 mg q 3
months (n = 105), 0.5 mg q 3
months (n = 14)
. 2nd extension study: 4 mg/yr of ZA
(n=22) or calcium only (n = 97)
2 years (n=19)
3 years (n=78)
5 years (n=22)

. PCB (n=3,876)
. 5 mg ZA infused over 15 min
(n=3,889)






. PCB (n=1,062)
. 5 mg ZA infused over 15 min
(n=1,065)
. Infusions administered <90 days
after surgical repair of hip fracture

. 5 mg ZA infused over 15 min
(n=69)
. Alendronate 70 mg weekly (n=59)




. single infusion of PCB plus 52
weeks of oral alendronate 70 mg
(n=112)
. 5 mg ZA infused over 15 min plus
52 weeks of oral placebo (n=113)






. 5 mg ZA infused over 15 minutes
(n=153)
. Alendronate 70 mg weekly
(n=148)


PCB = placebo

Pharma____ote___Volume___24,_ Issue____6_____March___2009_


. BMD increases similar in all the ZA
groups:
Spine values 4.3-5.1% higher
than placebo group (p<0.001)
Femoral neck values 3.1-3.5%
higher than placebo group
(p<0.001)

. BMD increases in all ZA subgroups:
Lumbar spine (6.4-9%), Proxi-
mal femur (4.9-5.5%),
Distal radius (2.2-3%), Total
body (3.6-5%)
. No evidence of progressive reduc-
tion of bone turnover markers;
Increased marker levels after
treatment discontinuation
. Drug regimen causes insufficient
reduction of remodeling activity in
one third of patients


. Reduction of vertebral fracture:
3.3% (ZA) vs 10.9% (PCB)
. Reduction of hip fracture:
1.4% (ZA) vs 2.5% (PCB)





. New clinical fracture:
8.6% (ZA) vs. 13.9% (PCB)





. ZA had a significantly greater re-
duction in mean urine NTx from
baseline (p<0.0001)
. 66.4% preferred annual IV therapy
vs. 19.7% weekly oral therapy

. Mean biomarker levels:
Alendronate remained at or
close to baseline levels
ZA reduced from baseline after
3 months, returned to baseline
after 6 months, and increased
thereafter but remained within
the premenopausal range
. 78.7% preferred yearly infusion


. Change in lumbar spine BMD rela-
tive to baseline:
6.1% increase (ZA) vs. 6.2%
increase (alendronate)


Black, et al.
(2007)19







Lyles, et al.
(2007)21





Saag, et al.
(2007)22





McClung, et al.
(2007)23










Novartis Corpora-
tion Internal Study
(2008)14


Volume 24, Issue 6 i March 2009


PharmaNote






prior to randomization (mean = 4 years). Study pa-
tients were assigned to either single dose of zole-
dronic acid 5 mg IV infused over 15 minutes plus
52 weeks of oral placebo (n=113) or one placebo IV
infusion plus 52 weeks of oral alendronate 70 mg
(n=112). Both groups were given calcium and vita-
min D supplementation. The primary endpoint of the
study was the percent change in lumbar spine BMD
from baseline to month 12. By the end of trial, zole-
dronic acid maintained BMD following the switch
from alendronate. Mean biomarker levels after 3
months were reduced from baseline; after 6 months,
returned to normal; and, increased thereafter but the
levels remained within the premenopausal range.
Over-all, reported adverse events were comparable
between the groups (zoledronic acid 86.7%, alendro-
nate 80.4%). Headache within the first 3 days post-
infusion however, occurred more frequently with
zoledronic acid (12.4%) vs. alendronate (6.3%).
There was less frequency of flu-like symptoms in
patients who switched from alendronate to zole-
dronic acid (0%) compared to previously reported by
Saag et a122 in bisphosphanate-naive patients given
zoledronic acid (18.8%). Once-yearly zoledronic
acid was preferred by the majority of the study par-
ticipants (78.7%). The investigators concluded that
patients can be switched from once-daily oral alen-
dronate to once-yearly IV zoledronic acid with main-
tenance of therapeutic effect for at least 12 months.23

Osteoporosis in Men
The efficacy and safety of zoledronic acid in men
with osteoporosis or significant osteoporosis secon-
dary to hypogonadism, were assessed in a 2-year ran-
domized, multicenter, double-blind, active controlled
trial involving 302 men aged 25-86 years (mean age
of 64). Study patients were randomly assigned to re-
ceive an annual single dose of 5 mg zoledronic acid
infused over 15 minutes (n=153) or a commercially
available oral weekly bisphosphonate, alendronate
(n=148). Both groups were supplemented with cal-
cium plus vitamin D. Zoledronic acid was noninfe-
rior to alendronate based on the percentage change in
lumbar spine BMD relative to baseline (zoledronic
acid: 6.1% increase; active control: 6.2% increase).
Adverse events reported were comparable between
the two groups except for the higher incidence of
post-dose symptoms in the zoledronic acid group,
which occurred within three days after the infusion.


The overall safety and tolerability of zoledronic acid
was similar to oral weekly alendronate.14


DOSING, ADMINISTRATION AND COST

Zoledronic acid is available as Reclast and Zo-
meta, approved for different indications. The rec-
ommended dose for Reclast in the treatment of os-
teoporosis in postmenopausal women and men is 5
mg intravenously administered over no less than 15
minutes once a year. Patients must be supplemented
with calcium and vitamin D if dietary intake is not
sufficient to prevent hypocalcemia. Acetaminophen
should be given at the time of IV infusion and at
home for the next 72 hours as needed to minimize
post-dose symptoms. Due to lack of clinical experi-
ence in patients with severe renal impairment, zole-
dronic acid is not recommended in patients with
creatinine claearance of <35 mL/min. Patients, espe-
cially those receiving diuretic therapy, should be ap-
propriately hydrated prior to administration of zole-
dronic acid to prevent impairment of kidneys. Zo-
meta, approved for treatment of malignancies, is
administered as 4 mg infused over no less than 15
minutes as a one time dose or every 3-4 weeks. Dose
adjustment is recommended in patients with baseline
creatinine clearance of <60 mL/min.14'16


SAFETY ISSUES

Osteonecrosis of the jaw (ONJ) has been associ-
ated with the use of bisphosphonate. King and Um-
land8 recently reviewed 44 published case reports
and case series involving 481 patients with bisphos-
phonate-related ONJ. They found that ONJ occurred
more frequently in patients receiving IV bisphospho-
nates (n=453, 94.2%) than those receiving oral
bisphosphonates (n=28, 5.8%); patients who had
cancer (n=451, 93.8%), most common diagnosis be-
ing multiple myeloma followed by breast, prostate
and lung cancers; and history of glucocorticoid use
(-75%). In the 449 patients who reported the inciting
event preceding ONJ diagnosis, 68.8% (n=309) had
tooth extraction or other surgical or invasive dental
procedure while 20.7% (n=93) developed ONJ spon-
taneously.8 Prescribers should perform a routine oral
examination prior to initiation of bisphosphonate
treatment. In patients with concomitant risk factors
(e.g., cancer, chemotherapy, radiotherapy, corticos-


Phraoe oue2, su Mrh20


Volume 24, Issue 6 1 March 2009


PharmaNote







Table 4: Cost of Bisphosphonates for Treatment of Osteoporosis9
DRUG DOSAGE ANNUAL COST* (USD)
Alendronate
Fosamax (Merck) 10 mg/d 1127.85
70 mg once/week 1093.04
Fosamax Plus D 70 mg + 2800 IU D3 once/week 1097.72
70 mg + 5600 IU D3 once/week 1084.20
Ibandronate
Boniva (Roche) 2.5 mg/d 1076.75
150 mg once/month 1030.68
3 mg IV every 3 months 1911.28
Risedronate
Actonel (Procter & Gamble) 5 mg/d 1076.75
35 mg once/week 1072.24
75 mg/day X 2 once/month 1078.08
Actonel with Calcium 35 mg once/week + 500 mg Ca other days of the week 1073.80
Zoledronic acid
Reclast (Novartis) 5 mg IV once/year 1262.00
*Cost of one year's treatment for the drug alone, based on September 30, 2007 data from Wolters Kluwer Health.


teroids, poor oral hygiene, pre-existing dental disease
or infection, anemia, coagulopathy), a dental exami-
nation with appropriate preventive dentistry should
be considered prior to treatment and invasive dental
procedures avoided while on treatment.14
The FDA did a one-year safety review to investi-
gate the concerns raised regarding the increased risk
of atrial fibrillation in bisphosphonate-treated pa-
tients. Placebo-controlled clinical trial data on
19,687 patients treated with bisphosphonate and
18,358 treated with placebo, followed for 6 months
to 3 years, were submitted by sponsors of alendro-
nate, ibandronate, risedronate, and zoledronic acid
upon FDA request. No clear association between
overall bisphosphonate exposure including increas-
ing dose or duration of therapy, and rate of serious or
non-serious atrial fibrillation was observed across all
studies. The FDA is exploring the feasibility of con-
ducting additional epidemiologic studies as they are
aware of the conflicting results from the literature
and other epidemiological studies. The FDA is also
continuing to do post-market report monitoring on
atrial fibrillation in bisphosphonate-treated patients.
On November 12, 2008, the FDA concluded that
healthcare professionals should not alter their pre-
scribing patterns for bisphosphonates and patients


should not stop taking their bisphosphonate medica-
tion. 24

SUMMARY

Bisphosphonates are the gold standard in the
treatment of osteoporosis. Due to the complexity of
oral bisphosphonate administration requirements and
adverse effects, patients' adherence to therapy de-
creases and eventually their osteoporosis worsens.
Available data on once-yearly IV infusion of zole-
dronic acid (Reclast) demonstrates that it is safe,
efficacious and well tolerated in both women and
men with osteoporosis. This dosing regimen may
increase adherence to therapy and ultimately im-
prove clinical outcomes.



REFERENCES

1. National Osteoporosis Foundation. Osteoporosis
fast facts. Available at: www.nof.org/osteoporosis/
diseasefacts.htm. Accessed January 18, 2009.
2. US Public Health Services Department of Health
and Human Services. Bone health and osteoporo-
sis: a report of the Surgeon General. Available at:


PharmaNote Volume 24, Issue 6 I March 2009


Volume 24, Issue 6 i March 2009


PharmaNote







www.surgeongeneral.gov/library/bonehealth/docs/
Chapter 4.pdf Accessed January 18, 2009.
3. Woodis CB. Once-yearly administered intrave-
nous zoledronic acid for postmenopausal osteopo-
rosis. Ann Pharmacother 2008;42:1085-9.
4. WHO Study Group on Assessment of Fracture
Risk and its Application to Screening for Post-
menopausal Osteoporosis 1994; World Health Or-
ganization, Geneva.
5. Lewiecki EW. Osteoporosis fracture risk assess-
ment. Available at www.uptodate.com. Accessed
January 18, 2009.
6. Lambrinoudaki I, Christodoulakos, Botsis D.
Bisphosphonates. Ann NY Acad Sci
2006;1092:397-402.
7. Miller PD. Optimizing the management of post-
menopausal osteoporosis with biphosphonate: the
emerging role of intermittent therapy. Clin Ther
2005;27:361-376.
8. King AE, Umland EM. Osteonecrosis of the jaw
in patients receiving intravenous or oral bisphos-
phonates. Pharmacother 2008;28(5):667-677.
9. A once-yearly IV bisphosphonate for osteoporosis.
Obstet Gynecol. 2008 May;111(5):1208-9.
10. Merck & Co., Inc. Fosamax (alendronate sodium)
package insert. Whitehouse Station, NJ; 2006.
11. Procter & Gamble Pharmaceuticals. Actonel
(risedronate sodium) package insert. Cincinnati,
OH; 2007.
12. Roche Laboratories. Boniva (ibandronate sodium
tablets) package insert. Nutley NJ; 2006.
13. Roche Laboratories. Boniva (ibandronate sodium
injection) package insert. Nutley NJ; 2007.
14. Novartis. Reclast (zoledronic acid) package insert.
East Hanover, NJ; 2008.
15. Cramer JA, Amonkar MM, Hebbom A, et al.
Compliance and persistence with bisphosphonate
dosing regimens among women with postmeno-
pausal osteoporosis. Curr Med Res Opin
2005;21:1453-60.
16. Novartis. Zometa (zoledronic acid) package insert.
East Hanover, NJ; 2005.
17. Reid IR, Brown JP, Burckhardt P, et al. Intrave-
nous zoledronic acid in postmenopausal women
with low bone mineral density. N Engl J Med
2002;346:653-61.
18. Devogelaer JP, Brown JP, Burckhardt P, et al.
Zoledronic acid efficacy and safety over five years
in postmenopausal osteoporosis. Osteoporos Int
2007;18:1211-8.
19. Black DM, Delmas PD, Eastell R, et al. Once-
yearly zoledronic acid for treatment of postmeno-


pausal osteoporosis. N Engl JMed 2007;356:1809
-22.
20. Colon-Emeric CS, Lyles KW, Mesenbrink P.
Zoledronate, fractures, and mortality after hip
fracture. Editorial. NEnglJMed. 2008 Feb 28;358
(9):967-8;968-9.
21. Lyles KW, Colon-Emeric CS, Magaziner JS, et al.
Zoledronic acid and clinical features and mortality
after hip fracture. N Engl J Med 2007;357:1799-
809.
22. Saag K, Lindsay R, Kriegman A, Beamer E, Wen-
chun Z. A single zoledronic cid infusion reduces
bone resorption markers more rapidly than weekly
oral alendronate in postmenopausal women with
low bone mineral ensity. Bone 2007;40:1238-43.
23. McClung M, Recker R, Miller P, et al. Intravenous
zoledronic acid 5 mg in the treatment of post-
menopausal women with low bone density previ-
ously treated with alendronate. Bone 2007;41:122-
8.
24. US FDA. Update of safety Review Follow-up to
the October 1, 2007 Early Communication about
the Ongoing Safety Review of Bisphosphonates.
Available at: http://www.fda.gov/Cder/Drug/
e a r 1 y c o m m /
bisphosphonatesupdate_200811 .htm. Accessed
January 23, 2009.
25. Johnson, BE. A once-yearly intravenous infusion
of zoledronic acid prevented fractures in post-
menopausal women with osteoporosis. Editorial.
ACP Journal Club. 2007 Sep/Oct;147(2):31.



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
PharmD, FCCP

R. Whit Curry, MD Associate Editor

Steven M. Smith Assistant Editor
PharmD


Elj yyyyyyyyyyy w


Phraoe oue2, su Mrh20


Volume 24, Issue 6 1 March 2009


PharmaNote




University of Florida Home Page
© 2004 - 2010 University of Florida George A. Smathers Libraries.
All rights reserved.

Acceptable Use, Copyright, and Disclaimer Statement
Last updated October 10, 2010 - - mvs