National PBM Drug Monograph

Zoledronic acid Injection (Reclast)

VHA Pharmacy Benefits Management Service and the Medical Advisory Panel

November 2008

*The purpose of VACO PBM drug monographs is to provide a comprehensive
drug review for making formulary decisions. These documents will be
updated when new clinical data warrant additional formulary discussion.
Documents will be placed in the Archive section when the information is
deemed to be no longer current.*

# Executive Summary: 

# Zoledronic acid (ZA), like other bisposphonates, is an inhibitor of osteoclastic-mediated bone resorption. {#zoledronic-acid-za-like-other-bisposphonates-is-an-inhibitor-of-osteoclastic-mediated-bone-resorption. .Style-Heading-1-+-Black}

-   Zoledronic acid has FDA approved labeling for the treatment of
    osteoporosis in postmenopausal women including patients at high risk
    of fracture, defined as a recent low-trauma hip fracture, and the
    treatment of Paget's disease of bone in men and women.

# Dose: a single 5 mg infusion administered over 15 minutes once a year. {#dose-a-single-5-mg-infusion-administered-over-15-minutes-once-a-year. .Style-Heading-1-+-Black}

# Zoledronic acid has demonstrated a faster onset of action as measured by suppression of biomarkers of bone turnover and formation.  {#zoledronic-acid-has-demonstrated-a-faster-onset-of-action-as-measured-by-suppression-of-biomarkers-of-bone-turnover-and-formation. .Style-Heading-1-+-Black}

# The HORIZON Pivotal Fracture Trial demonstrated that over 3-year period an annual 5 mg ZA infusion significantly reduced the risk of vertebral, hip and other fractures in postmenopausal women. {#the-horizon-pivotal-fracture-trial-demonstrated-that-over-3-year-period-an-annual-5-mg-za-infusion-significantly-reduced-the-risk-of-vertebral-hip-and-other-fractures-in-postmenopausal-women. .Style-Heading-1-+-Black}

# The HORIZON Recurrent Fracture Trial concluded that a yearly infusion of ZA within 90 days of repair of a low-trauma hip fracture was associated with reduced risk for new clinical fractures with improved survival. {#the-horizon-recurrent-fracture-trial-concluded-that-a-yearly-infusion-of-za-within-90-days-of-repair-of-a-low-trauma-hip-fracture-was-associated-with-reduced-risk-for-new-clinical-fractures-with-improved-survival. .Style-Heading-1-+-Black}

# In a pooled analysis of 2 six month clinical trials with 18 month extensions, a single 5 mg infusion of ZA produced a more rapid, more complete and longer therapeutic response than risedronate in patients with Paget's disease. {#in-a-pooled-analysis-of-2-six-month-clinical-trials-with-18-month-extensions-a-single-5-mg-infusion-of-za-produced-a-more-rapid-more-complete-and-longer-therapeutic-response-than-risedronate-in-patients-with-pagets-disease. .Style-Heading-1-+-Black}

-   Zoledronic acid is not recommended for patients with a creatinine
    clearance \<35 mL/minute

# Zoledronic acid's adverse effect profile is similar to the other bispophonates and includes serious effects such as ocular complications, the risk for osteonecrosis of the jaw, atrial fibrillation, renal impairment, and hypocalcemia. {#zoledronic-acids-adverse-effect-profile-is-similar-to-the-other-bispophonates-and-includes-serious-effects-such-as-ocular-complications-the-risk-for-osteonecrosis-of-the-jaw-atrial-fibrillation-renal-impairment-and-hypocalcemia. .Style-Heading-1-+-Black}

# The annual cost for a ZA 5mg infusion is \$747.21 compared to \$267.80 for weekly 70 mg oral dose of alendronate.  {#the-annual-cost-for-a-za-5mg-infusion-is-747.21-compared-to-267.80-for-weekly-70-mg-oral-dose-of-alendronate. .Style-Heading-1-+-Black}

# Introduction {#introduction .Style-Heading-1-+-Black}

The purposes of this monograph are to (1) evaluate the available
evidence of safety, tolerability, efficacy, cost, and other
pharmaceutical issues that would be relevant to evaluating zoledronic
acid (ZA) 5 mg infusion for possible addition to the VA National
Formulary; (2) define its role in therapy; and (3) identify parameters
for its rational use in the VA.

# Pharmacology/Pharmacokinetics^1^ {#pharmacologypharmacokinetics1 .Style-Heading-1-+-Black}

Zoledronic acid, like other bisphosphonates, is an inhibitor of
osteoclastic-mediated bone resorption specifically targeting farnesyl
pyrophosphate synthase in the osteoclast. Zoledronic acid has the
highest binding affinity to bone mineral of all the bisphosphonates
which accounts for its long duration of action.

No information is available on the pharmacokinetics of ZA in patients
with osteoporosis or Paget's disease. Data are available from patients
with cancer and bone metastases.

Table 1. Pharmacokinetics of Zoledronic Acid

  ------------------------- ---------------------------------------------
  **Parameter**             

  Time to Peak              End of infusion

  Metabolism                Not metabolized

  Elimination               39% recovered unchanged after 24 hours

  Half-life                 146 hours

  Protein Binding           28%-53% in vitro

  Bioavailability           100%
  ------------------------- ---------------------------------------------

# FDA Approved Indication(s) and Off-label Uses^1^

Zoledronic acid (as Reclast) has FDA approved labeling for the treatment
of osteoporosis in postmenopausal women, including patients at high risk
of fracture, defined as a recent low-trauma hip fracture, and the
treatment of Paget's disease of bone in men and women.

Potential off-label uses for ZA include treatment of osteoporosis in men
and glucocorticoid- or anticonvulsant-induced osteoporosis.

# Current VA National Formulary Alternatives

Alendronate and risedronate, both oral bisphosphonates, have approved
labeling for the prevention and treatment of osteoporosis in
postmenopausal women, treatment to increase bone mass in men with
osteoporosis, the treatment of glucocorticoid-induced osteoporosis in
men and women, and the treatment of Paget's disease of the bone in men
and women.

# Dosage and Administration^1^

*Dosage:*

Postmenopausal osteoporosis: Yearly 5 mg intravenous infusion over 15
minutes.

Paget's disease: A single 5 mg intravenous infusion given over 15
minutes.

*Dosage in Special Populations:*

[Hepatic Impairment]{.underline}: No information is available.
Zoledronic acid is not metabolized.

[Renal Impairment]{.underline}: Zoledronic acid should not administered
to patients with a creatinine clearance \<35 mL/min. Dose adjustment is
not necessary for patients whose creatinine clearance is
[\>]{.underline}35 ml/min.

[Elderly]{.underline}: There are no specific dose adjustments based up
age. See Renal Impairment.

*Administration:*

Zoledronic acid 5 mg comes in a 100 mL ready to use sterile solution
(containing 4950 mg of mannitol, USP and 30 mg of sodium citrate, USP in
water for injection, USP) is to be infused over a minimum of 15 minutes
at a constant infusion rate. If refrigerated, the solution should be
allowed to reach room temperature prior to administration. The solution
should not come into contact with any calcium or other divalent
cation-containing solutions and should be administered through a
separate vented infusion line.

*Storage:*

Store at 25^o^C (77^o^F); excursions permitted to 15^o^C-30^o^C
(59^o^F-86^o^F). After opening the solution, it is stable for 23 hours
at 2^o^C-8^o^C (36^o^F-46^o^F).

**[Efficacy in Osteoporosis and Paget's Disease]{.underline}**^2-8^

[Outcome Measures]{.underline}

Bone Resorption:

-   Urine N-telopeptide of type I collagen (NTX)

-   Serum C-telopeptide of type I collagen (β-CTX)

Bone Formation:

-   Serum bone-specific alkaline phosphatase (BSAP)

-   serum osteocalcin

-   N-terminal propeptide of type I collagen (P1NP)

Bone Mineral Density (BMD)

Fracture rate:

-   Morphometric vertebral fractures

-   Clinical fractures -- hip, vertebrae, wrist, etc...

[Phase II Dose Finding Study]{.underline}^2^

The dose and dosing interval of ZA was investigated in a Phase II
clinical trial of postmenopausal women with a BMD at L1 -- L4
[\>]{.underline}2 standard deviations (SD) below a T-score of -2.
Outcome was assessed by changes in BMD (lumbar spine, non-dominant
proximal femur and forearm, and total body) as measured by dual-energy
x-ray absorptiometry (DXA) and changes in biomarkers of bone turnover,
NTX and β-CTX, and bone formation, BSAP and serum osteocalcin, at
baseline, 6, 9 and 12 months.

Postmenopausal women between 45-80 years of age were randomized in a
double-blind manner to one of six treatment arms: ZA infusion of 0.25
mg, 0.5 mg, or 1 mg every 3 months; 2 mg every 6 months for 2 doses; a
single 4 mg dose; or placebo every 3 months. All treatment arms received
an infusion every 3 months of either active medication or placebo.

Three hundred sixteen of the 351 women randomized completed the trial.
Baseline characteristics did not differ significantly between the six
treatment groups. The percent changes in BMD at the lumbar spine (4.3% -
5.1% at 12 months) and femoral neck (3.1% - 3.5% at 12 months) were
significantly greater in all ZA groups than placebo at all time points.
There were no significant differences between any of the ZA groups.
Differences in changes in BMD at the distal radius were smaller (0.8% -
1.6% at 12 months), yet significant from placebo except between placebo
and ZA 0.25 mg. Similar small, yet significant, differences were
reported for changes in total body BMD (0.9% - 1.3% at 12 months) except
between ZA 0.5 mg and placebo. Biomarkers of bone turnover and bone
formation were significantly suppressed by all doses of ZA.

[Speed of Onset: ZA vs. Alendronate]{.underline}^3^

In order to compare the speed of onset of action between a single 5 mg
dose of ZA and a weekly 70 mg dose of alendronate (for 24-weeks),
investigators conducted an international, multicenter, randomized,
double-blind, double-dummy, active controlled clinical trial in
postmenopausal women between 45 and 79 years of age. Study entry
required a T score [\<]{.underline} -2 at the lumbar spine or femoral
neck within 3 months of screening. Subjects who'd taken a bisphosphonate
within the previous 2 years were ineligible unless their lifetime
exposure was less than 8 weeks and there had been no exposure in the 6
months prior to randomization. Subjects who'd ever taken sodium
fluoride, strontium ranelate or parathyroid hormone were ineligible as
were those who'd been treated with raloxifene, calcitonin, tibolone or
hormone replacement therapy (HRT) within 6 months prior to randomization
or whose CrCl was less than 30 mL/min. Subjects were randomized in a 1:1
ratio of ZA to alendronate. All subjects received 1000 mg/day of
elemental calcium and 400 IU/day of vitamin D during the study.

Change from baseline in biochemical markers were used as outcome
measures, specifically, NTX and β-CTX were used to assess the rate of
bone resorption while BSAP functioned as a measure of bone formation.
Urine NTX and serum β-CTX were measured at baseline and on weeks 1, 2,
4, 8, 12, and 24; serum BSAP was measured at baseline and weeks 4, 12
and 24. The study's primary endpoint was the change in NTX after the
first-week of treatment (one week after the dose of ZA or the initial
dose of alendronate). Patient preference to treatment modality and
dyspepsia symptoms were secondary outcome measures. An
intention-to-treat analytical approach was employed.

One hundred twenty-eight subjects were randomized: 69 to ZA and 59 to
placebo. Compliance exceeded 85% in both groups with respect to oral
alendronate or oral placebo. Baseline demographic, NTX, β-CTX, and BSAP
values did not differ significantly. At the one week point, the mean NTX
concentration was significantly lower in the ZA group than the
alendronate group, p\<0.0001 (Table 2). The mean NTX concentration in
the ZA group gradually increased between weeks 1 and 12, while they
continued to decrease in the alendronate group until week 12. There was
essentially no change in NTX concentrations between weeks 12 and 24 in
either group, with the change from baseline in the ZA group
significantly greater (p\<0.05) than in the alendronate group at all
points. The reductions in serum β-CTX concentrations followed a similar
path as NTX. Mean serum BSAP declined over time in both groups, but the
two groups differed only after 12 weeks (p\<0.0001).

**Table 2. Changes in Biomarkers of Bone Turnover**

+-----------------------+-----------------------+-----------------------+
| **Biochemical         | **Zoledronic Acid**   | **Alendronate**       |
| Marker**              |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Urine NTX, nmol       | 46.11 (24.211)        | 45.82 (20.788)        |
| BCE/mmol Cr           |                       |                       |
|                       | 15.2 (1.128)          | 35.5 (2.600)          |
| -   Baseline, mean    |                       |                       |
|     (SD)              |                       |                       |
|                       |                       |                       |
| -   After 1-week,     |                       |                       |
|     mean (SE)         |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Serum β-CTX, ng/mL    | 0.443 (0.212)         | 0.429 (0.174)         |
|                       |                       |                       |
| -   Baseline, mean    |                       |                       |
|     (SD)              |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Serum BSAP, ng/mL     | 16.80 (7.749)         | 16.85 (7.893)         |
+-----------------------+-----------------------+-----------------------+

Subjects preferred the once yearly infusion of ZA to the once weekly
oral dose of alendronate for convenience (66.4% vs. 15.6%), satisfaction
(59.8% vs. 18.9%), willingness to take for a long period of time (68%
vs. 15.6%), and overall preference (66.4% vs. 19.7%). Six subjects in
the ZA group (4 secondary to adverse events) and 5 in the alendronate
group (3 secondary to adverse events) discontinued the study prior to
its completion.

The authors concluded that a single 5 mg intravenous dose of zoledronic
acid produced more rapid and greater reduction biological markers of
bone turnover and formation than a once weekly 70 mg dose of alendronate
over a 24-week study. A single ZA infusion was preferred by most
subjects compared to weekly oral dosing.

In a study designed to demonstrate the non-inferiority of ZA to
alendronate in maintaining BMD of the lumbar spine, 255 postmenopausal
women between 45 to 79 years of age were randomized to receive a single
5 mg iv dose of ZA or a weekly 70 mg oral dose of alendronate for 52
weeks. The multicenter study used a double-blind and double dummy
design. All subjects received 1000 mg of elemental calcium and 400 IU of
vitamin D daily. Eligibility requirements included having been treated
with alendronate for [\>]{.underline}1 year prior to randomization and a
T-score of [\<]{.underline} -2.0 at the lumbar spine or femoral neck
prior to starting alendronate. Study outcome measures included DXA scans
at the PA lumbar spine (L1-L4) at baseline and after 12 months, and
biochemical markers of bone turnover (NTZ and β-CTX) and bone formation
(BSAP and P1NP) collected at baseline, 3, 6, 9 and 12 months. Bone
biopsies following tetracycline labeling were preformed on a subset of
subjects to assess microscopic appearance and bone histomorphometric
parameters. At the study's conclusion, subjects were asked their
treatment preferences. Statistical analysis was performed according to
ITT and modified ITT (MITT) principles. The MITT included all subjects
who'd taken at least one dose of study medication and had baseline and
12 month BMD results available. Conditions for non-inferiority were
satisfied if the lower limit of the 95% confidence interval for the
difference in percent change from baseline in lumbar spine BMD was not
below -1.5%.

Totals of 113 and 112 subjects were randomized to ZA and alendronate,
respectively; the two groups did not differ in baseline demographics,
disease characteristics, or biomarker values. Alendronate had been used
for approximately 4 years on average prior to randomization. A small
positive mean percent change (SE) from baseline in lumbar spine BMD was
found in both treatment groups after 12 months, regardless of analysis:
ITT with LOCF: ZA 0.167 (0.258) and alendronate 0.813 (0.283); mean
difference between groups -0.646 (95% CI -1.400, 0.108) and MITT; ZA
0.12 (0.273) and alendronate 0.828 (0.288); mean difference between
groups -0.708 (-1.491, 0.075). The authors concluded that the predefined
criteria for non-inferiority had been met. Biomarkers in the ZA group
fluctuated over the 12 month period, initially declined significantly by
3 months, returning to baseline at 6 months and increasing over the next
6 months, but remaining in the premenopausal reference range. In the
alendronate group, biomarkers varied little compared to baseline values
over the 12 month period. Bone biopsies from 23 of the 25 subjects were
sufficient for analysis; all were normal in appearance and indicated
bone remodeling had continued with both treatments. Ninety-eight percent
of subjects completed the treatment preference questionnaire: 78.7%
preferred the once a year infusion, 9% the weekly oral dose, and 11.8%
expressed equal preference.

[HORIZON (Health Outcomes and Reduced Incidence with Zoledronic Acid
Once Yearly)]{.underline} ^5,\ 6^

Two HORIZON trials have been published to date: the pivotal fracture and
recurrent fracture trials.

The purpose of the HORIZON Pivotal Fracture Trial was to evaluate
whether ZA reduced the risk of vertebral, hip and other types of
fractures. This multicenter, double-blind, placebo controlled trial
randomized postmenopausal women ages 65 to 89 years to either ZA 5 mg or
placebo annually for 3 doses; both were administered as 100 mL infusions
over 15 minutes. Participants received oral calcium (1000-1500 mg) and
vitamin D (400-1200 mg) daily. To be eligible participants must have had
a BMD T-score of [\<]{.underline}-2.5 at the femoral neck, without an
existing vertebral fracture, or a T-score of [\<]{.underline}-1.5 with
radiologic evidence of 2 or more mild vertebral factures or one modest
vertebral fracture. Subjects who'd previously taken a bisphosphonate
must have had a suitable washout period based on duration of exposure to
be eligible. Participants were allowed to use hormone therapy,
raloxifene, calcitonin, tibolone, tamoxifen, dehydroepiandrosterone,
ipriflavone and medroxyprogesterone during the study. For the analysis,
women were stratified as to there use of osteoporosis medication at
baseline: strata 1 nonusers, strata 2 users. Other exclusion criteria
included ever taking of strontium, sodium fluoride, or parathyroid
hormone; use of growth hormone or anabolic steroids in the previous 6
months; or us of systematic glucocorticoids in the previous 12 months; a
serum calcium concentration above or below a specified range, a
creatinine clearance \<30 mL/min or 2+ protein on a urine dipstick.

Participants were seen in clinic at baseline and at months 6, 12, 24,
and 36; quarterly contact was made through telephone interviews. The
study's primary endpoints were new vertebral fractures for Stratum 1 and
hip fracture for Stratums 1 and 2. Secondary measures of efficacy were
non-vertebral fracture, any clinical fracture, and clinical vertebral
fracture. Changes in BMD (total hip, femoral neck, and lumbar spine) as
measured by DXA as well as changes in total height and biomarkers of
bone turnover (β-CTX) and bone formation (BSAP, P1NP) were other
secondary outcome measures (Table 3). Vertebrae from T4 to L4 were
evaluated by an expert at a central location. Incident morphometric
vertebral fractures were defined as a [\>]{.underline}20% reduction in
vertebrae height and a [\>]{.underline}4 mm decrease in qualitative
morphometry.

**Table3. Frequency of Outcome M**easures

  --------------------- -------------- ---------- ---------- ---------- ----------
  **Measure**           **Baseline**   **6        **12       **24       **36
                                       Months**   Months**   Months**   Months**

  Spinal lateral        X                         X          X          X
  radiograph                                                            

  Clinical fracture     X              X          X          X          X
  report\*                                                              

  Height                X                         X          X          X

  DXA, hip              X              X          X          X          X

  Biomarkers\*\*        X              X          X          X          X
  --------------------- -------------- ---------- ---------- ---------- ----------

\*Collected during quarterly calls; \*\*only collected in a cohort of
\~600 subjects

A total of 3889 women were randomized to ZA and 3876 to placebo. Nearly
100% of randomized subjects were included in the efficacy (99.6%) and
safety (99.3%) analyses. Eighty-four percent of participants were
followed for the 3 years and 81% received all 3 doses of study
medication. Participants did not differ with respect to baseline
characteristics; the mean age was 73 years and 78.7% and 78.6% of
subjects in the ZA and placebo arms were in stratum 1, respectively.

Based upon the 3 year incidence of morphometric fractures, the
percentages of subjects in stratum 1 identified with a new vertebral
fracture were 10.9% in the placebo arm and 3.3% in the ZA arm. The
difference between groups was significant at each yearly time point. The
relative risk (RR) of vertebral fracture in stratum 1 was reduced by 70%
in the ZA group (RR 0.30, 95% CI, 0.24-0.38). The incidence of hip
fracture in all subjects was 2.5% in the placebo arm and 1.4% in the ZA
arm (Hazard ratio (HR) 0.59, 0.42-0.83). The findings of all secondary
fracture end points favored ZA over placebo: non-vertebral fracture
10.7% placebo and 8% ZA (HR 0.75, 0.64-0.87); any clinical fracture
12.8% vs. 8.4% (HR 0.67, 0.58-0.77); clinical vertebral fracture 2.6%
vs. 0.5% (HR 0.23, 0.14-0.37) and multiple morphometric vertebral
fracture (stratum 1 only) 2.3 % vs.0.2% (RR0.11, 0.05-0.023). After 3
years the absolute difference in change from baseline in BMD
significantly favored ZA at the total hip (6.02%, 95% CI 5.77-6.28),
lumbar spine (6.71%, 5.69-7.74) and femoral neck (5.06%, 4.76-5.36). The
loss of height was lower in ZA subjects (-4.2 mm) compared with those
assigned to placebo (-7.0 mm, p\<0.001). Subjects in the ZA arm had
significantly greater reductions in all 3 biomarkers compared to those
in the placebo arm at the12 month mark; these measures remained
relatively constant over the final 24 months of the trial.

The authors of the HORIZON Pivotal Fracture Trial concluded that over
3-year period an annual 5 mg ZA infusion significantly reduced the risk
of vertebral, hip and other fractures.

The HORIZON Recurrent Fracture Trial was designed to test the efficacy
and safety of ZA for the prevention of new clinical fractures in men and
women following recent surgical repair of a hip fracture. Participant's
in this multicenter, international double-blind, placebo-controlled
study were randomized to receive either an infusion of 5 mg ZA or
placebo within 90 days following the surgical repair of a hip fracture
and annually for the study's duration. Study participants also received
loading doses of vitamin D~3~ or D~2~ for 14 days prior to their first
infusion if their serum 25-hydroxyvitamin D concentration as
[\<]{.underline}15 ng/mL or was not available. Following the first
infusion, subjects received oral calcium ( 1000 to 1500 mg) and vitamin
D (800-1200 mg) daily.

In addition to a recent non-traumatic hip fracture, participants must
have been \>50 years of age. Participants were allowed concurrent us of
nasal calcitonin, serum estrogen receptor modulators, hormone
replacement, tibolone, and external hip protectors at the discretion of
the investigators. Previous users of bisphosphonates and parathyroid
hormone were eligible provided the washout period was sufficient for the
duration of use. Participants were not eligible if they'd taken
strontium or sodium fluoride. Other exclusion criteria included a
creatinine clearance \<30 mL/min, corrected serum calcium \>11 mg/dL or
\<8 mg/dL, life expectancy of \<6 months, active caver or other
metabolic bone disease. During the trial if a subject's BMD at the total
hip declined to prespecified values at specific time points or they
experienced a clinical fracture, the subject had the option to start a
nonbisphosphonate osteoporosis medication (with the exception of
teriparatide) and continue in the trial; or start an oral bisphosphonate
or teriparatide, and discontinue study participation but continue to be
followed; or discontinue study participation entirely.

The study's primary endpoint was a new clinical fracture (excluding
fractures of the face, digits or of abnormal bone). Secondary endpoints
were changes in BMD as measured annually by DXA in the non-fractured
hip; new vertebral, nonvertebral and hip fracture; and pre-specified
safety endpoints.

Randomization resulted in 1065 subjects being assigned to ZA and 1062 to
placebo; 71.3% completed the trial with a median follow-up time of 1.9
years. One or more new clinical fractures (424 in total) were
experienced by 139 subjects in the placebo arm and 92 subjects assigned
to ZA; cumulative percentages of 13.9% and 8.6%, respectively. After 24
months, treatment with ZA resulted in risk reductions of 35% for any new
fracture at 24 months (HR 0.65, 95%CI 0.5-0.84); 27% for non-vertebral
fractures (0.73, 0.32-0.92); 46% for new vertebral factures (0.54,
0.32-0.92); and a nonsignificant 30% reduction for new hip fractures
(0.70, 0.41-1.19).

The study's safety analysis included 1054 and 1057 subjects from the ZA
and placebo groups, respectively. Death was reported for 9.6% of
subjects in the ZA group and 13.3% in the placebo group. The risk for
death was reduced by 28% in the ZA group (HR0.72, 95% CI 0.56-0.93).

Secondary outcome measures show that the change from baseline was a
lower BMD in the placebo arm and an increase in the ZA arm; p\<0.001 for
all comparisons (Table 4).

**Table 4. Percent change from baseline in BMD at the hip and femoral
neck**

+-----------------------+-----------------------+-----------------------+
| **Site**              | **Placebo**           | **Zoledronic acid**   |
+-----------------------+-----------------------+-----------------------+
| Hip                   | -1.09                 | +2.6                  |
|                       |                       |                       |
| -   12 months         | -0.7                  | +4.7                  |
|                       |                       |                       |
| -   24 month          | -0.9                  | +5.5                  |
|                       |                       |                       |
| -   36 months         |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Femoral Neck          | -1.7                  | +0.8                  |
|                       |                       |                       |
| -   12 months         | -2.1                  | +2.2                  |
|                       |                       |                       |
| -   24 months         | -0.7                  | +3.6                  |
|                       |                       |                       |
| -   36 months         |                       |                       |
+-----------------------+-----------------------+-----------------------+

The authors of the HORIZON Recurrent Fracture Trial concluded that a
yearly infusion of ZA within 90 days of repair of a low-trauma hip
fracture was associated with reduced risk for new clinical fractures
with improved survival.

**Efficacy in Paget's Disease of the Bone^7,\ ^**^8^

Two identical randomized, double-blind clinical trials compared the
efficacy of a single 5 mg infusion of ZA (n=177) to risedronate 30 mg
per day for 60 days (n=172) in men and women 30 years and older with
Paget's disease. All subjects received 1000 mg of calcium and 400 to
1000 IU of calciferol per day. The primary efficacy endpoint was a
normalization of alkaline phosphatase concentration or a \>75% reduction
in total alkaline phosphatase excess 6 months after treatment. Secondary
and exploratory efficacy end points included biomarkers of bone
resorption (β-CTX, and the ratio of urine ~ά~C-telopeptide of type I
collagen to creatinine) and bone formation (serum N-terminal propeptide
of type I collagen); and quality of life as measured by the Medical
Outcomes Study 36-item Short-Form General Health Survey (SF-36). Both
studies were powered to demonstrate ZA's noninferiority to risedronate
with respect to the percentage of subjects meeting the primary efficacy
endpoint.

Results of the two trials were pooled. Baseline characteristics did not
differ between groups and adherence was 98.3% in the risedronate group
and 93.2% in the ZA group. A therapeutic response was achieved by 96% of
the ZA group and 74.3% of the risedronate group after 6 month
(p\<0.001). A normalized alkaline phosphatase concentrations was
achieved in 88.6% of ZA subjects and 57.9% of risedronate subjects
(p\<0.001). The median time to a therapeutic response was 64 days for ZA
and 89 days for risedronate (p\<0.001). Mean concentrations of the 3
biomarkers of bone resorption and formation declined more rapidly in the
ZA group achieving a significant difference from risedronate 10 days
after the first dose and maintaining this difference over the remainder
of the study period (p\<0.001). Within 63 days of infusion the mean
value for all 3 biomarkers in the ZA group declined to and remained
within the normal range for premenopausal women; at no time did any mean
value in the risedronate group decline to within these ranges. The
physical-component summary of the SF-36 increased from baseline at 3 and
6 months in ZA group and differed from those in the risedronate group at
3 months. Pain scores improved in both groups.

Participants who responded to either treatment (n=296) were eligible to
participate in an 18 month extension trial to determine the long-term
efficacy and relapse rate; 267 (90.2%) agreed to continue. During the
extension trial no bisphosphonate was given. The primary outcome measure
was the same as during the initial 6 month trials and biomarkers were
obtained every 6 months during the extension trial. Mean serum alkaline
phosphate concentrations remained constant throughout the extension in
ZA group (no change from initial response) with 98% of those in the ZA
maintaining a therapeutic response after 24 months. In the risedronate
group, mean serum alkaline phosphate concentrations rose during the
extension trial with 57% maintaining a therapeutic response at the end
of extension trial (24 months).

The authors of these trials concluded that a single 5 mg infusion of ZA
produced a more rapid, more complete and longer therapeutic response
than risedronate in patients with Paget's disease.

# Adverse Events (Safety Data) ^1-8^ 

## Deaths and Other Serious Adverse Events 

Atrial fibrillation was reported as an adjudicated serious adverse event
in 1.3% (50/3862) postmenopausal women who received ZA and 0.4%
(17/3852) who received placebo. The overall incidence of atrial
fibrillation in the ZA treatment group was 2.5% and 1.9% in the placebo
group. Greater than 90% of these events took place more than 30 days
after the infusion. There were no differences in the incidence of atrial
fibrillation between treatments in a sub-set of subjects (n=559) who
received an ECG prior to and 9-11 days after infusion.

Cases of iritis/uveitis/episcleritis/conjunctivitis have been reported
in patients treated with bisphosphonates including ZA. Nine
postmenopausal women (0.2%) assigned to ZA and one (\<0.1%) assigned to
placebo developed iritis/uveitis/episcleritis.

## Common Adverse Events

Acute phase reactions including fever (19%), myalgia (9%) and flu-like
symptoms (8%), headache 7% and arthralgia (7%) were reported following
ZA infusion. These symptoms were more common in the first 3 days of
treatment and usually resolved within 3 days, but may have taken up to
14 days. The frequency of the events decreased with subsequent doses
(Tables 5, 6, 7)

**Table 6. Adverse Events Occurring in \>2% of Postmenopausal
Osteoporotic Women Over 3-years**

+-----------------------+-----------------------+-----------------------+
| **Adverse Event**     | **IV ZA 5 mg          | **IV Placebo          |
|                       | Annually, %'**        | Annually, %**         |
|                       |                       |                       |
|                       | **N=3862**            | **N=3852**            |
+-----------------------+-----------------------+-----------------------+
| Anemia                | 4.4                   | 3.6                   |
+-----------------------+-----------------------+-----------------------+
| Anorexia              | 2.0                   | 1.1                   |
+-----------------------+-----------------------+-----------------------+
| Headache              | 12.4                  | 8.1                   |
|                       |                       |                       |
| Dizziness             | 7.6                   | 6.7                   |
+-----------------------+-----------------------+-----------------------+
| Hypertension          | 12.7                  | 12.4                  |
+-----------------------+-----------------------+-----------------------+
| Vertigo               | 4.3                   | 4.0                   |
+-----------------------+-----------------------+-----------------------+
| Atrial fibrillation   | 2.4                   | 1.9                   |
+-----------------------+-----------------------+-----------------------+
| Nausea                | 8.5                   | 5.2                   |
|                       |                       |                       |
| Diarrhea              | 6.0                   | 5.6                   |
|                       |                       |                       |
| Vomiting              | 4.6                   | 3.2                   |
|                       |                       |                       |
| Abdominal pain        | 4.6                   | 3.1                   |
|                       |                       |                       |
| Dyspepsia             | 4.3                   | 4.0                   |
+-----------------------+-----------------------+-----------------------+
| Arthralgia            | 23.8                  | 20.4                  |
|                       |                       |                       |
| Myalgia               | 11.7                  | 3.7                   |
|                       |                       |                       |
| Pain in extremity     | 11.3                  | 9.9                   |
|                       |                       |                       |
| Shoulder pain         | 6.9                   | 5.6                   |
|                       |                       |                       |
| Bone pain             | 5.8                   | 2.3                   |
|                       |                       |                       |
| Neck pain             | 4.4                   | 3.8                   |
|                       |                       |                       |
| Muscle spasms         | 3.7                   | 3.4                   |
+-----------------------+-----------------------+-----------------------+
| Pyrexia               | 17.9                  | 4.6                   |
|                       |                       |                       |
| Flu-like symptoms     | 8.8                   | 2.7                   |
|                       |                       |                       |
| Fatigue               | 5.4                   | 3.5                   |
|                       |                       |                       |
| Chills                | 5.4                   | 1.0                   |
|                       |                       |                       |
| Asthenia              | 5.3                   | 2.9                   |
|                       |                       |                       |
| Peripheral edema      | 4.6                   | 4.2                   |
|                       |                       |                       |
| Pain                  | 3.3                   | 1.3                   |
|                       |                       |                       |
| Malaise               | 2.0                   | 1.0                   |
+-----------------------+-----------------------+-----------------------+

**Table 7.** Adverse Events in Women with Osteoporosis Receiving ZA or
Alendronate Over 6-months

+--------------------+---------+---------+-------------+------------+
| **Adverse Event**  | **IV ZA |         | **          |            |
|                    | 5 mg, % |         | Alendronate |            |
|                    | (       |         | 70 mg/week, |            |
|                    | N=69)** |         | % (N=172)** |            |
+--------------------+---------+---------+-------------+------------+
|                    | **Days  | **After | **Days      | **After    |
|                    | 1-3**   | Day 3** | 1-3**       | Day 3**    |
+--------------------+---------+---------+-------------+------------+
| Any                | 63.8    | 79.7    | 37.3        | 78.0       |
|                    |         |         |             |            |
| Flu-like illness   | 18.8    | 1.4     | 5.1         | 1.7        |
|                    |         |         |             |            |
| Nausea             | 11.6    | 1.4     | 5.1         | 6.8        |
|                    |         |         |             |            |
| Myalgia            | 11.6    | 7.2     | 1.7         | 3.4        |
|                    |         |         |             |            |
| Headache           | 7.2     | 8.7     | 11.9        | 15.3       |
|                    |         |         |             |            |
| Arthralgia         | 7.2     | 5.8     | 6.8         | 10.2       |
|                    |         |         |             |            |
| Pain               | 7.2     | 0       | 1.7         | 0          |
|                    |         |         |             |            |
| Dyspepsia          | 5.8     | 10.1    | 3.4         | 5.1        |
|                    |         |         |             |            |
| Pyrexia            | 5.8     | 0       | 1.7         | 1.7        |
|                    |         |         |             |            |
| Back pain          | 5.8     | 2.9     | 0           | 6.8        |
|                    |         |         |             |            |
| Chills             | 5.8     | 1.4     | 0           | 1.7        |
|                    |         |         |             |            |
| Flatulence         | 4.3     | 1.4     | 0           | 3.4        |
|                    |         |         |             |            |
| Chest pain         | 4.3     | 1.4     | 0           | 1.7        |
|                    |         |         |             |            |
| Rash               | 4.3     | 1.4     | 0           | 1.7        |
|                    |         |         |             |            |
| Dizziness          | 4.3     | 0       | 0           | 5.1        |
|                    |         |         |             |            |
| Fatigue            | 2.9     | 2.9     | 5.1         | 1.7        |
|                    |         |         |             |            |
| Diarrhea           | 2.9     | 4.3     | 0           | 6.8        |
|                    |         |         |             |            |
| Extremity pain     | 1.4     | 2.9     | 3.4         | 6.8        |
|                    |         |         |             |            |
| Shoulder pain      | 1.4     | 0       | 0           | 5.1        |
|                    |         |         |             |            |
| Abdominal pain     | 1.4     | 0       | 1.4         | 5.1        |
|                    |         |         |             |            |
| Abdominal          | 0       | 2.9     | 0           | 6.8        |
| distension         |         |         |             |            |
|                    | 0       | 10.1    | 0           | 3.4        |
| Nasopharyngitis    |         |         |             |            |
|                    | 0       | 7.2     | 0           | 11.9       |
| Upper respiratory  |         |         |             |            |
| tract infect.      |         |         |             |            |
+--------------------+---------+---------+-------------+------------+

**Table 8. Adverse Events Occurring in Patients with** Paget's Receiving
ZA or Risedronate Over 6-months

+------------------+---+---------+---------+--------------+--------------+
| **Adverse        |   | **IV ZA |         | *            |              |
| Event**          |   | 5 mg, % |         | *Risedronate |              |
|                  |   | (N      |         | 30 mg/day x  |              |
|                  |   | =177)** |         | 2 months, %  |              |
|                  |   |         |         | (N=172)**    |              |
+------------------+---+---------+---------+--------------+--------------+
|                  |   | **Days  | **After | **Days 1-3** | **After Day  |
|                  |   | 1-3**   | Day 3** |              | 3**          |
+------------------+---+---------+---------+--------------+--------------+
| Any              | 5 |         | 66.1    | 25.0         | 73.3         |
|                  | 3 |         |         |              |              |
| Flu-like illness | . |         | 4.0     | 4.1          | 5.8          |
|                  | 7 |         |         |              |              |
| Myalgia          |   |         | 2.3     | 3.5          | 7.0          |
|                  | 9 |         |         |              |              |
| Pyrexia          | . |         | 5.1     | 0.6          | 2.9          |
|                  | 6 |         |         |              |              |
| Fatigue          |   |         | 5.1     | 2.3          | 8.1          |
|                  | 7 |         |         |              |              |
| Headache         | . |         | 4.5     | 4.1          | 5.2          |
|                  | 3 |         |         |              |              |
| Rigors           |   |         | 7.3     | 0.6          | 7.0          |
|                  | 7 |         |         |              |              |
| Nausea           | . |         | 5.1     | 1.7          | 11.0         |
|                  | 3 |         |         |              |              |
| Bone pain        |   |         |         | 1.2          |              |
|                  | 6 |         |         |              |              |
| Back pain        | . |         |         |              |              |
|                  | 8 |         |         |              |              |
| Dizziness        |   |         |         |              |              |
|                  | 6 |         |         |              |              |
| Nasopharyngitis  | . |         |         |              |              |
|                  | 8 |         |         |              |              |
| Diarrhea         |   |         |         |              |              |
|                  | 6 |         |         |              |              |
| Pain in arm or   | . |         |         |              |              |
| leg              | 8 |         |         |              |              |
|                  |   |         |         |              |              |
| Arthralgia       | 6 |         |         |              |              |
|                  | . |         |         |              |              |
|                  | 2 |         |         |              |              |
|                  |   |         |         |              |              |
|                  | 5 |         |         |              |              |
|                  | . |         |         |              |              |
|                  | 1 |         |         |              |              |
+------------------+---+---------+---------+--------------+--------------+

## Other Adverse Events

# Infusion site reactions such as itching, redness, and/or pain were reported in 0.7% of postmenopausal women following infusion of ZA compared to 0.5% administered placebo. 

# Precautions/Contraindications^1^

## Precautions

-   Zoledronic acid is not recommended for patients with a creatinine
    clearance \<35 mL/minute

-   Osteonecrosis of the jaw has been reported with the bisphosphonates
    including zoledronic acid. A routine oral exam should be performed
    on all patients prior to treatment.

-   Bronchoconstricton has been reported in patients with
    aspirin-sensitivity after receiving a bisphosphonate; no cases have
    been reported with ZA.

-   Renal impairment has been observed following the administration of
    ZA, especially in those with pre-existing renal compromise or other
    risk factors (chemotherapy, diuretic use, etc.) Patients should be
    well hydrated prior to receiving ZA.

-   Musculoskeletal pain has been reported with all bisphosphonates and
    can occur within a day to several months following initiation of
    therapy. Consider withholding future doses of ZA if severe symptoms
    develop.

[Use in Pregnancy and Lactation]{.underline}

FDA Pregnancy Category D: Zoledronic acid should not be used during
pregnancy and fetal exposure may be harmful. Women of childbearing
potential should be advised to avoid pregnancy while receiving ZA.

It is unknown whether ZA is excreted into human milk. Women who are
breast feeding an infant should not receive ZA and ZA should not be
given to nursing women.

## Contraindications

-   Hypocalcemia. Pre-existing hypocalcemia and disturbances of mineral
    metabolism must be effectively treated before initiating treatment
    with ZA. Hypocalcemia is a significant risk following the
    administration of ZA to patients with Paget's disease.

-   Hypersensitivity to any component of zoledronic acid.

-   Patients should not be receiving other ZA products, i.e., Zometa,
    when receiving Reclast.

# Look-alike / Sound-alike (LA / SA) Error Risk Potential

The VA PBM and Center for Medication Safety is conducting a pilot
program which queries a multi-attribute drug product search engine for
similar sounding and appearing drug names based on orthographic and
phonologic similarities, as well as similarities in dosage form,
strength and route of administration. Based on similarity scores as well
as clinical judgment, the following drug names [may]{.underline} be
potential sources of drug name confusion:

LA/SA for generic name: **Zoledronic acid**: Zoladex, Zoloft, zolpidme,
zonidamide, Zosyn

LA/SA for trade name: **Reclast**: Requip, Reglan, reclipren

LA/SA for trade name: **Zometa**: Zebeta, Zosyn, Byetta, Zomig

# Drug Interactions^1^

## Drug-Drug Interactions

No *in vivo* drug interaction studies have been conducted with ZA.
Zoledronic acid's pharmacokinetic profile suggests that it has a low
probability for *in vivo* drug-drug interactions.

Concurrent use of ZA with aminoglycosides may have an additive effect to
lower serum calcium concentrations.

Concurrent use of ZA with loop diuretics may increase the risk for
hypocalcemia.

Caution is indicated when ZA is used with other potentially nephrotoxic
drugs such as nonsteroidal anti-inflammatory drugs.

## Drug-Lab Interactions

None known.

# Acquisition Costs

Table 9. Current VA Prices for Bisphosphonates

  ----------------------------- ----------------- ------------- ---------------
  **Drug**                      **^\#^Cost/Dose   **Cost/30     **Cost/year
                                (\$)**            days (\$)**   (\$)**

  Zoledronic acid 5 mg          747.21            Na            747.21

  Alendronate 10 mg (daily)     0.74              22.20         270.10

  Alendronate 70 mg (weekly)    5.15              20.60         267.80

  Risedronate 5 mg tablets      1.16              34.80         417.60
  (daily)                                                       

  Risedronate 35 mg tablets     8.11              32.44         389.28
  (weekly)                                                      
  ----------------------------- ----------------- ------------- ---------------

# ^\#^Price in effect on 11/6/2008 and do not reflect any rebates, discounts or subsequent price changes.

# Pharmacoeconomic Analysis

A pharmacoeconomic model has been developed by the manufacturers for ZA
that analyzes ZA's cost effectiveness and budget impact to a health care
system relative to other bisphosphonates. Variables included in the
model are yearly net cost of treatment (including co pay, laboratory
monitoring, and administration costs), the plan's population
demographics, each medication's efficacy rate for the reducing the risk
of vertebral, hip, and non-vertebral fractures, patient compliance and
the incidence and cost of treating fractures. VA data available for
inclusion in the model were drug cost, co pay, current utilization, cost
of treating a hip fracture, and patient demographics. Model default
values were used for cost of treating vertebral and non-vertebral costs,
fracture incidence, while drug efficacy rates were based on
manufacturers' package inserts. Assumptions included that efficacy rates
based largely on women would apply to a predominantly male patient
population. Variables adjusted in various models included compliance,
drug acquisition cost, and market share of alendronate and ZA. The base
and adjusted values for the variables used in the model are provided in
Table 10.

**Table 10. Variables Included in the Cost Effectiveness and Budget
Impact Models**

+-----------+----------+----------+-----------+-----------+-----------+
| **V       | **ZA 5mg | **Alend  | **Rise    | **Terip   | **Iban    |
| ariable** | I        | ronate** | dronate** | aratide** | dronate** |
|           | V/year** |          |           |           |           |
|           |          | **70     | **35      | **750 mcg | **3 mg IV |
|           |          | m        | mg/week** | pen**     | q3 mo.**  |
|           |          | g/week** |           |           |           |
+-----------+----------+----------+-----------+-----------+-----------+
| [^\*^Drug | 774.90   | 20.      | 32.44     | 419.00    | 299.80    |
| Costs,    |          | 60/10.30 |           |           |           |
| \$]{.u    | 774.90   |          | 389.28    | 5028.00   | 1199.20   |
| nderline} |          | 247.2    |           |           |           |
|           | 0        | 0/123.60 | 96.00     | 96.00     | 0         |
| Cost/dose |          |          |           |           |           |
|           | 774.90   | 96.      | 293.28    | 4932.00   | 1199.20   |
| Cost/year |          | 00/96.00 |           |           |           |
|           |          |          |           |           |           |
| Co        |          | 151.     |           |           |           |
| pay/year  |          | 20/27.60 |           |           |           |
|           |          |          |           |           |           |
| Net       |          |          |           |           |           |
| cost/year |          |          |           |           |           |
+-----------+----------+----------+-----------+-----------+-----------+
| [Efficacy | 70%      | 48%      | 41%       | 65%       | 52%       |
| Rates]{.u |          |          |           |           |           |
| nderline} | 41%      | 29%      | 29%       | 47%       | 29%       |
|           |          |          |           |           |           |
| Vertebral | 25%      | 27%      | 36%       | 53%       | 25%       |
| fx        |          |          |           |           |           |
|           |          |          |           |           |           |
| Hip fx    |          |          |           |           |           |
|           |          |          |           |           |           |
| Nonvert.  |          |          |           |           |           |
| Fx        |          |          |           |           |           |
+-----------+----------+----------+-----------+-----------+-----------+
| C         | 100%     | 60%/80%  | 60%/80%   | 100%      | 100%      |
| ompliance |          |          |           |           |           |
+-----------+----------+----------+-----------+-----------+-----------+
| [Market   | 0        | 92%      | 7%        | 0.65%     | 0.45%     |
| Share]{.u |          |          |           |           |           |
| nderline} | 5%/25%   | 88%/67%  | 6%/7%     | 0.65%     | 0         |
|           |          |          |           |           |           |
| Current   |          |          |           |           |           |
|           |          |          |           |           |           |
| Adjusted  |          |          |           |           |           |
+-----------+----------+----------+-----------+-----------+-----------+

^\*^Drug cost prior to price reduction to \$747.21

**Table 11. Cost Effective Analysis B**ased on Compliance and
Alendronate Cost

+-----------+---------+-----------+---------+-----------+-------------+
| **V       | **ZA    | **Alen    | *       | **Terip   | **Ib        |
| ariable** | 5mg     | dronate** | *Risedr | aratide** | andronate** |
|           | IV      |           | onate** |           |             |
|           | /year** | **70      |         | **750 mcg | **3 mg IV   |
|           |         | mg/week** | **35    | pen**     | q3 mo.**    |
|           |         |           | mg      |           |             |
|           |         |           | /week** |           |             |
+-----------+---------+-----------+---------+-----------+-------------+
| **Model   |         |           |         |           |             |
| A: Oral   |         |           |         |           |             |
| bisph     |         |           |         |           |             |
| osphonate |         |           |         |           |             |
| 60%       |         |           |         |           |             |
| C         |         |           |         |           |             |
| ompliance |         |           |         |           |             |
| &         |         |           |         |           |             |
| al        |         |           |         |           |             |
| endronate |         |           |         |           |             |
| \$20.6    |         |           |         |           |             |
| 0/month** |         |           |         |           |             |
+-----------+---------+-----------+---------+-----------+-------------+
| [Total/pt | 1       | 1,582.63  | 1       | 5,824.42  | 2,851.64    |
| cost,     | ,914.00 |           | ,662.67 |           |             |
| \$]{.u    |         | 3.80%     |         | 11.68%    | 7.86%       |
| nderline} | 9.98%   |           | 3.77%   |           |             |
|           |         | 41,664.62 |         | 49,887.96 | 36,266.55   |
| 52        | 19      |           | 44      |           |             |
| week/pt   | ,188.06 |           | ,079.40 |           |             |
|           |         |           |         |           |             |
| Fx        |         |           |         |           |             |
| avoided   |         |           |         |           |             |
|           |         |           |         |           |             |
| Cost/fx   |         |           |         |           |             |
| avoided   |         |           |         |           |             |
+-----------+---------+-----------+---------+-----------+-------------+
| [In       |         | 22,476.56 | 24      | 30,699.90 | 17,078.49   |
| cremental |         |           | ,891.34 |           |             |
| CE ratio: |         |           |         |           |             |
| ZA        |         |           |         |           |             |
| vs.]{.u   |         |           |         |           |             |
| nderline} |         |           |         |           |             |
|           |         |           |         |           |             |
| Per fx    |         |           |         |           |             |
| avoided   |         |           |         |           |             |
+-----------+---------+-----------+---------+-----------+-------------+
| **Model   |         |           |         |           |             |
| B: Oral   |         |           |         |           |             |
| bisph     |         |           |         |           |             |
| osphonate |         |           |         |           |             |
| 60%       |         |           |         |           |             |
| C         |         |           |         |           |             |
| ompliance |         |           |         |           |             |
| &         |         |           |         |           |             |
| al        |         |           |         |           |             |
| endronate |         |           |         |           |             |
| \$10.3    |         |           |         |           |             |
| 0/month** |         |           |         |           |             |
+-----------+---------+-----------+---------+-----------+-------------+
| [Total/pt | 1       | 1,508.47  | 1       | 5,824.42  | 2,851.64    |
| cost,     | ,914.01 |           | ,662.67 |           |             |
| \$]{.u    |         | 3.80%     |         | 11.68%    | 7.86%       |
| nderline} | 9.98%   |           | 3.77%   |           |             |
|           |         | 39,712.27 |         | 49,887.96 | 36,266.55   |
| 52        | 19      |           | 44      |           |             |
| week/pt   | ,188.06 |           | ,079.40 |           |             |
|           |         |           |         |           |             |
| Fx        |         |           |         |           |             |
| avoided   |         |           |         |           |             |
|           |         |           |         |           |             |
| Cost/fx   |         |           |         |           |             |
| avoided   |         |           |         |           |             |
+-----------+---------+-----------+---------+-----------+-------------+
| [In       |         | 20,524.21 | 24      | 30,699.90 | 17,078.49   |
| cremental |         |           | ,891.34 |           |             |
| CE ratio: |         |           |         |           |             |
| ZA        |         |           |         |           |             |
| vs.]{.u   |         |           |         |           |             |
| nderline} |         |           |         |           |             |
|           |         |           |         |           |             |
| Per fx    |         |           |         |           |             |
| avoided   |         |           |         |           |             |
+-----------+---------+-----------+---------+-----------+-------------+
| **Model   |         |           |         |           |             |
| C: Oral   |         |           |         |           |             |
| bisph     |         |           |         |           |             |
| osphonate |         |           |         |           |             |
| 80%       |         |           |         |           |             |
| C         |         |           |         |           |             |
| ompliance |         |           |         |           |             |
| &         |         |           |         |           |             |
| al        |         |           |         |           |             |
| endronate |         |           |         |           |             |
| \$10.3    |         |           |         |           |             |
| 0/month** |         |           |         |           |             |
+-----------+---------+-----------+---------+-----------+-------------+
| [Total/pt | 1       | 1,338.24  | 1542.15 | 5,824.42  | 2,851.64    |
| cost,     | ,914.01 |           |         |           |             |
| \$]{.u    |         | 6.31%     | 6.26%   | 11.68%    | 7.86%       |
| nderline} | 9.98%   |           |         |           |             |
|           |         | 21,223.42 | 24      | 49,887.96 | 36,266.55   |
| 52        | 19      |           | ,629.02 |           |             |
| week/pt   | ,188.06 |           |         |           |             |
|           |         |           |         |           |             |
| Fx        |         |           |         |           |             |
| avoided   |         |           |         |           |             |
|           |         |           |         |           |             |
| Cost/fx   |         |           |         |           |             |
| avoided   |         |           |         |           |             |
+-----------+---------+-----------+---------+-----------+-------------+
| [In       |         | 2,035.36  | 5       | 30,699.90 | 17,078.49   |
| cremental |         |           | ,440.96 |           |             |
| CE ratio: |         |           |         |           |             |
| ZA        |         |           |         |           |             |
| vs.]{.u   |         |           |         |           |             |
| nderline} |         |           |         |           |             |
|           |         |           |         |           |             |
| Per fx    |         |           |         |           |             |
| avoided   |         |           |         |           |             |
+-----------+---------+-----------+---------+-----------+-------------+

The costs for treating fractures used in the model were hip fracture,
\$69,389 (Medicare cost), vertebral facture \$1,378 and nonvertebral
facture \$3,028.

The above findings reflect the cost per fracture avoided in accordance
with three models that vary patient compliance and the acquisition cost
of alendronate 70 mg taken weekly. Compliance data for VA were not
available (medication possession ratio). A 60% compliance rate was
chosen as the lower limit at it was the lower limit from a VA data set
on compliance with statin therapy and corresponds to a 10% probability
of fracture and 33% of therapeutic efficacy.^9^ Compliance rates of 80%
and 100% correspond with a 9% and 8% probability of fracture and a 67%
and 100% therapeutic efficacy.^9^ Based on these and other model inputs,
cost per fracture avoided with ZA would be \$19,188.06 in each model
while the incremental cost avoided with ZA compared to alendronate
ranges from \$2,035.36 to \$22,476.56 and is positive with all other
comparison agents.

**Table 12. Budget Impact Analysis Based on Compliance, Alendronate Cost
& Market Share:**

**Additional Cost Per Member Per Month (PMPM)**

+----------------+----------------+----------------+-----------------+
| **Model A:     |                |                |                 |
| Oral           |                |                |                 |
| bisphosphonate |                |                |                 |
| 60% Compliance |                |                |                 |
| & alendronate  |                |                |                 |
| \              |                |                |                 |
| $20.60/month** |                |                |                 |
|                |                |                |                 |
| Market Share   |                |                |                 |
| (Curr          |                |                |                 |
| ent/Adjusted): |                |                |                 |
| ZA 0/5%,       |                |                |                 |
| alendronate    |                |                |                 |
| 92%/88%,       |                |                |                 |
| risedronate    |                |                |                 |
| 7%/6%,         |                |                |                 |
| teriparatide   |                |                |                 |
| 0.65%/0.65%,   |                |                |                 |
| ibandronate iv |                |                |                 |
| 0.45%/0        |                |                |                 |
+----------------+----------------+----------------+-----------------+
| [PMPM          | [Curren        | [Adjuste       | [Differen       |
| Cost           | t]{.underline} | d]{.underline} | ce]{.underline} |
| s]{.underline} |                |                |                 |
|                | \$ 1.11        | \$ 1.37        | \$0.26          |
| Treatment      |                |                |                 |
|                | \$12.22        | \$11.99        | -\$0.23         |
| Fracture       |                |                |                 |
|                | \$13.33        | \$13.35        | \$0.02          |
| Total          |                |                |                 |
+----------------+----------------+----------------+-----------------+
| **Model B:     |                |                |                 |
| Oral           |                |                |                 |
| bisphosphonate |                |                |                 |
| 60% Compliance |                |                |                 |
| & alendronate  |                |                |                 |
| \              |                |                |                 |
| $10.30/month** |                |                |                 |
|                |                |                |                 |
| Market Share   |                |                |                 |
| (Curr          |                |                |                 |
| ent/Adjusted): |                |                |                 |
| ZA 0/5%,       |                |                |                 |
| alendronate    |                |                |                 |
| 92%/88%,       |                |                |                 |
| risedronate    |                |                |                 |
| 7%/6%,         |                |                |                 |
| teriparatide   |                |                |                 |
| 0.65%/0.65%,   |                |                |                 |
| ibandronate iv |                |                |                 |
| 0.45%/0        |                |                |                 |
+----------------+----------------+----------------+-----------------+
| [PMPM          | [Curren        | [Adjuste       | [Differen       |
| Cost           | t]{.underline} | d]{.underline} | ce]{.underline} |
| s]{.underline} |                |                |                 |
|                | \$ 0.55        | \$ 0.83        | \$0.28          |
| Treatment      |                |                |                 |
|                | \$12.22        | \$11.99        | -\$0.23         |
| Fracture       |                |                |                 |
|                | \$12.77        | \$12.82        | \$0.05          |
| Total          |                |                |                 |
+----------------+----------------+----------------+-----------------+
| **Model C:     |                |                |                 |
| Oral           |                |                |                 |
| bisphosphonate |                |                |                 |
| 80% Compliance |                |                |                 |
| & alendronate  |                |                |                 |
| \              |                |                |                 |
| $10.30/month** |                |                |                 |
|                |                |                |                 |
| Market Share   |                |                |                 |
| (Curr          |                |                |                 |
| ent/Adjusted): |                |                |                 |
| ZA 0/5%,       |                |                |                 |
| alendronate    |                |                |                 |
| 92%/88%,       |                |                |                 |
| risedronate    |                |                |                 |
| 7%/6%,         |                |                |                 |
| teriparatide   |                |                |                 |
| 0.65%/0.65%,   |                |                |                 |
| ibandronate iv |                |                |                 |
| 0.45%/0        |                |                |                 |
+----------------+----------------+----------------+-----------------+
| [PMPM          | [Curren        | [Adjuste       | [Differen       |
| Cost           | t]{.underline} | d]{.underline} | ce]{.underline} |
| s]{.underline} |                |                |                 |
|                | \$ 0.63        | \$ 0.90        | \$0.28          |
| Treatment      |                |                |                 |
|                | \$10.79        | \$10.63        | -\$0.16         |
| Fracture       |                |                |                 |
|                | \$11.41        | \$11.53        | \$0.11          |
| Total          |                |                |                 |
+----------------+----------------+----------------+-----------------+
| **Model D:     |                |                |                 |
| Oral           |                |                |                 |
| bisphosphonate |                |                |                 |
| 60% Compliance |                |                |                 |
| & alendronate  |                |                |                 |
| \              |                |                |                 |
| $20.60/month** |                |                |                 |
|                |                |                |                 |
| Market Share   |                |                |                 |
| (Curr          |                |                |                 |
| ent/Adjusted): |                |                |                 |
| ZA 0/25%,      |                |                |                 |
| alendronate    |                |                |                 |
| 92%/67%,       |                |                |                 |
| risedronate    |                |                |                 |
| 7%/7%,         |                |                |                 |
| teriparatide   |                |                |                 |
| 0.65%/0.65%,   |                |                |                 |
| ibandronate iv |                |                |                 |
| 0.45%/0.45%    |                |                |                 |
+----------------+----------------+----------------+-----------------+
| [PMPM          | [Curren        | [Adjuste       | [Differen       |
| Cost           | t]{.underline} | d]{.underline} | ce]{.underline} |
| s]{.underline} |                |                |                 |
|                | \$ 1.11        | \$ 2.73        | \$1.62          |
| Treatment      |                |                |                 |
|                | \$12.22        | \$11.27        | -\$0.94         |
| Fracture       |                |                |                 |
|                | \$13.33        | \$14.01        | \$0.68          |
| Total          |                |                |                 |
+----------------+----------------+----------------+-----------------+

In all four models the cost per member per month to the VA is greater,
ranging from \$0.02 to \$0.68, depending on compliance rate, cost of
alendronate and market share shift from alendronate to ZA.

# 

# Conclusions

Zoledronic acid has demonstrated efficacy in the treatment of
postmenopausal osteoporosis and in the treatment of Paget's disease in
men and women. A recent AHRQ meta-analysis concluded there is no overall
difference in the bisphosphosphonates efficacy. Zoledronic acid is
unique from other available bisphosphonates in the treatment of
postmenopausal osteoporosis and Paget's disease as it is administered
once a year and appears to have a faster onset of action as measured by
biomarkers of bone turnover and formation. Zoledronic acid is the only
bisphosphonates to have been studied when started within 90 days
following the surgical repair of a hip fracture; demonstrating safety
and efficacy while bone is still healing as well as improved survival
compared to placebo.

Zoledronic acid's limitations to the VA include the absence of
information on its efficacy and tolerability in men. No subset analysis
is available of those trials that included men. At present additional
clinical trials are planned or underway for additional labeling
indications including for the treatment of osteoporosis in men and
glucocorticoid- and anticonvulsant-induced osteoporosis. Another
limitation is its cost, presently \$747 annually per patient plus the
related costs of the infusion (personnel, setup, and infusion chair).

# References:

1\. Zoledronic acid (Reclast) package insert, 2007.

2\. Reid IR, Brown JP, Burckhardt P, et al. Intravenous zoledronic acid
in postmenopausal women with

low bone mineral density. N Engl J Med 2002;346:653-61.

3\. Saag K, Lindsay R, Kriegman A, et al. A single zoledronic acid
infusion reduces bone resorption

markers more rapidly than weekly oral alendronate in postmenopausal
women with low bone mineral

density. Bone 2007;40:1238-43.

4\. McClung M, Recker R, Miller P, et al. Intravenous zoledronic acid 5
mg in the treatment of

postmenopausal women with low bone density previously treated with
alendronate. Bone2007;41:122-

8\.

5\. Black DM, Delmas PD, Eastell R, et al. Once-yearly zoledronic acid
for treatment of postmenopausal

osteoporosis. N Engl J Med 2007;356:1809-22.

6\. 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.

7\. Reid IR, Miller P, Lyles K, et al. Comparison of a single infusion
of zoledronic acid with risedronate

for Paget's disease. N Engl J Med 2005;353:898-908.

8\. Hosking D, Lyles K, Brown JP, et al. Long-term control of bone
turnover in Paget's disease with

zoledronic acid and risedronate. Bone 2007;22:142-8.

9\. Siris ES, Harris ST, Rosen CJ, et al. Adherence to bisphosphonate
therapy and fracture rates in

osteoporotic women: relationship to vertebral and nonvertebral fractures
in 2 US claims databases.

Mayo Clin Proc 2006;81:1013-22.

**Contact person: Todd Semla, MS, Pharm.D., BCPS, FCCP, AGSF**