National PBM Drug Monograph

Ibandronate Sodium Tablets and Injection (Boniva®)

January 2008

VHA Pharmacy Benefits Management Services and the Medical Advisory Panel

*The purpose of VACO PBM Services 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when the information is deemed to be no longer current.*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: 

-   Ibandronate is a nitrogen-containing bisphosphonate agent that
    inhibits bone resorption and turnover.

-   Oral daily (2.5 mg) and monthly (150 mg) and intravenous (IV)
    quarterly (3 mg) formulations of ibandronate are available and FDA
    approved in the prevention (oral) and treatment (IV and oral) of
    osteoporosis in postmenopausal women.

-   In the pivotal BONE trial, ibandronate 2.5 mg oral daily was shown
    to be more effective than placebo in decreasing morphometric
    vertebral fractures and increasing lumbar spine and hip bone mineral
    density (BMD) in a total of 2929 postmenopausal women with
    osteoporosis and baseline vertebral fractures. No significant
    reduction in nonvertebral fractures was observed.

-   Ibandronate 150 mg oral monthly was shown to be noninferior to the
    established 2.5 mg daily regimen in increasing lumbar spine and hip
    BMD in women with osteoporosis in the MOBILE trial. In addition, the
    150 mg monthly regimen was associated with statistically superior
    increases in lumbar spine and hip BMD. No significant differences in
    adverse events between groups were observed.

-   The ibandronate 3 mg quarterly IV formulation was shown to be
    noninferior to the oral daily 2.5 mg dose in increasing lumbar spine
    and hip BMD in the DIVA trial in postmenopausal women with
    osteoporosis. A similar incidence of side effects between groups was
    noted in the 1-year interim results.

-   In the Prevention study, 2.5 mg oral ibandronate daily was shown to
    be effective in improving and normalizing BMD in postmenopausal
    osteopenic women.

-   Ibandronate is not approved for the treatment of osteoporosis in
    men, and evidence in this patient population is very limited.

-   Ibandronate appears well tolerated and similar to other
    bisphosphonates in its side effect profile. Common side effects
    include upper gastrointestinal (GI) upset and musculoskeletal
    symptoms.

# 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 ibandronate
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^1-3^ {#pharmacologypharmacokinetics1-3 .Style-Heading-1-+-Black}

Ibandronate sodium is a nitrogen-containing bisphosphonate agent that
decreases bone resorption and turnover through the inhibition of
osteoclast activity.

Bioavailability and pharmacokinetics of ibandronate sodium are
comparable in men and women. Similar to other bisphosphonates (i.e.,
alendronate and risedronate), oral absorption of ibandronate sodium is
low and is further reduced by ingestion of food and beverages (other
than plain water).

Table 1. Pharmacokinetic Parameters of Ibandronate^2^\*

  ----------------------------------- -----------------------------------
  **Parameter**                       **Ibandronate**

  Bioavailability (Fasting)           0.6%

  Protein Binding                     85.7 -- 99.5%

  Metabolism                          Not Metabolized

  Elimination                         Renal

  Terminal Half-life                  37-157 hrs\*
  ----------------------------------- -----------------------------------

\*Observed apparent half-life based on 150 mg oral dose. The true
terminal elimination half-life is dependent on dose and sensitivity of
assay used and is likely to be longer and similar to other
bisphosphonates.

# FDA Approved Indication(s) and Off-label Uses ^1-3^

Ibandronate sodium tablets are indicated for the prevention and
treatment of osteoporosis in postmenopausal women; ibandronate sodium
injection is indicated for the treatment of osteoporosis in
postmenopausal women.

Off-label uses of ibandronate include the treatment of osteoporosis in
men, corticosteroid-induced osteoporosis, and Paget's disease.

# Current VA National Formulary Alternatives

The bisphosphonates alendronate and risedronate are therapeutic
alternatives currently listed on the VA National Formulary.

# Dosage and Administration ^1-3^

**Oral**

Ibandronate is available in 2.5 mg and 150 mg tablets. The recommended
dose of ibandronate for the treatment of postmenopausal osteoporosis
(PMO) is 2.5 mg once daily or 150 mg once monthly, given on the same
date each month. For prevention of PMO, the recommended dose of
ibandronate is 2.5 mg daily; 150 mg monthly may be considered as an
alternative.

For maximal drug absorption, ibandronate should be taken with plain
water at least 60 minutes prior to the first food or drink of the day
and prior to taking any oral medications (including supplements). To
minimize the risk for esophageal irritation, ibandronate tablets should
be swallowed whole with 6-8 oz of water, and patients should remain in
an upright position (either standing or sitting) for 60 minutes
following administration.

**Injection**

Ibandronate is available in a 3 mg/3ml solution for injection in a
prefilled syringe. The recommended dose of ibandronate injection is 3 mg
given every 3 months, administered by a healthcare professional as an
intravenous bolus over 15-30 seconds.

All patients should have adequate intake of calcium (at least 1200
mg/day) and vitamin D (400-800 IU/day).

**Special Populations**

*Elderly*

No dosage adjustments are recommended in the elderly. Patients \>65
years of age comprised greater than 50% of the population in the major
clinical trials with ibandronate tablets and injection. No overall
difference in safety and effectiveness was noted between patients \>65
years old and younger patients, although the manufacturer states that
greater sensitivity in certain elderly individuals cannot be ruled out.
Age-related decline in renal function may alter the elimination of
ibandronate in this population (see Renal Impairment below).

*Hepatic Impairment*

No dosage adjustments are recommended in patients with hepatic
impairment, as the drug is not metabolized by the liver.

*Renal Impairment*

No dosage adjustments are recommended in patients with mild to moderate
renal impairment (creatinine clearance ≥30 ml/min). Ibandronate is not
recommended for use in patients with severe renal impairment (i.e.,
creatinine clearance \<30 ml/min or serum creatinine \>2.3 mg/dL).
Compared to those with normal renal function, exposure was 55% higher in
patients with a creatinine clearance between 40 and 70 ml/min and
greater than 2-fold higher in patients with a creatinine clearance \<30
ml/min following a single IV dose of ibandronate.

# Storage

The tablets and prefilled syringe should be stored at room temperature
(25°C) with excursions between 15-30°C (59-86°F) permitted.

# Efficacy 

## Efficacy Measures^4,5^

Although fracture reduction is the preferred outcome measure in
osteoporosis investigation, the surrogate marker of change in bone
mineral density (BMD) is often used in clinical trials. Studies that
evaluate fracture reduction require a large patient population and long
duration of study to detect significant differences between treatments.
Although measuring BMD is the gold standard in diagnosing osteoporosis,
the ability to predict fracture risk using BMD is imperfect. BMD is
accurately and commonly measured at the lumbar spine and hip by dual
energy x-ray absorptiometry (DXA).

Primary Efficacy Endpoints

-   Morphometric vertebral fracture

-   Changes in BMD at lumbar spine and hip

Secondary and Other Efficacy Endpoints

-   Clinical vertebral and non-vertebral fractures (often reported as
    adverse events)

-   Biochemical markers of bone turnover

-   Height loss

-   Safety and tolerability

## Summary of efficacy findings (See Appendix for additional information on clinical trials)

*Treatment of Osteoporosis in Postmenopausal Women*

The efficacy of ibandronate in the treatment of women with PMO has been
demonstrated in four pivotal clinical trials; two evaluating oral
regimens and two evaluating the injectable formulation. The BONE and
fracture prevention trials were superiority studies that measured
fracture incidence as the primary endpoint. The MOBILE and DIVA studies
were comparative noninferiority trials that investigated changes in BMD
as the primary outcome measure.

BONE was a randomized, double-blind, placebo-controlled study that
compared oral ibandronate given in a daily regimen (2.5 mg/day), an
intermittent regimen (20 mg every other day x12 doses every 3 months),
and placebo in a total of 2946 women with osteoporosis and baseline
vertebral fracture.^6^ Following 3 years of treatment, both ibandronate
regimens were associated with a significantly lower incidence of new
morphometric vertebral fractures compared to placebo: 4.7% (95% CI
3.2-6.2) with the daily regimen; 4.9% (95% CI 3.4-6.4) with the
intermittent regimen; 9.6% (95% CI 7.5-11.7) with placebo. Similar and
significant improvements in spine and hip BMD were observed with both
ibandronate regimens vs. placebo as shown below (see Table 2). Although
lower rates of clinical vertebral fractures occurred in the ibandronate
groups, no difference in the incidence of non-vertebral fractures vs.
placebo was shown. Ibandronate treatment was associated with sustained
and significant improvements in markers of bone turnover (in a
predefined subpopulation of 20%) and decreased loss of height.

MOBILE was a randomized, double-blind, noninferiority trial of two years
duration that compared three monthly oral ibandronate regimens (50 mg
daily x2 days once monthly; 100 mg once monthly; and 150 mg once
monthly) to the established daily regimen (2.5 mg daily) in a total of
1609 women with PMO.^7,8^ Efficacy measures were analyzed based on the
per-protocol population (n=1277) due to the noninferiority design. For
the primary endpoint of change in lumbar spine BMD, all monthly regimens
were found to be at least as effective as the daily regimen (see Table 2
below). Additionally, in a prospectively defined analysis, the 150 mg
monthly regimen was statistically superior to the daily regimen in the
primary measure. All regimens were associated with significant
improvements in hip BMD (total hip, femoral neck, and trochanter), and
the 100 mg and 150 mg dose statistically superior to the daily dose.
Significant decreases in the bone resorption marker C-telopeptide of the
alpha-chain of type I collagen (sCTX) were also observed with all
regimens. Analysis performed on the ITT population produced consistent
results regarding BMD outcomes.

Based on results from previous IV dose ranging studies, the IV fracture
prevention study, a phase III randomized, placebo-controlled trial of 3
years duration was conducted in 2862 postmenopausal women with
osteoporosis and baseline fracture.^1,10^ This study failed to reach its
primary endpoint, and the cumulative incidence of new morphometric
vertebral fractures was not significantly different between ibandronate
treatment groups (ibandronate 0.5 mg or 1 mg IV given every 3 months)
and placebo. Dose dependent increases in lumbar spine and hip BMD were
reported in both ibandronate groups, but the statistical significance
was not stated. Recker et al. concluded that larger doses may be needed
to produce more substantial increases in BMD and potentially reducing
fracture risk.

DIVA was a two year, randomized, double-blind, double-dummy
noninferiority trial that compared two higher dose regimens of
ibandronate injection (2 mg IV every 2 months and 3 mg IV every 3
months) to the established daily regimen (2.5 mg/day). One year results
are published at this time.^9^ In the per-protocol population of 1104
women with PMO, the primary efficacy endpoint of mean change in lumbar
spine BMD was shown to be noninferior in both ibandronate injection
groups compared to oral treatment at one year (see Table 2 below).
Further, both injection groups were found to be statistically superior
to the oral ibandronate group with respect to lumbar spine BMD
improvements in a prospectively defined analysis. Both ibandronate
injection regimens were at least as effective as oral treatment in
increasing hip BMD. In a similar preplanned analysis, injectable
ibandronate was shown to be more effective than oral treatment.
Significant and sustained decreases of sCTX were observed in all
treatment arms. Analysis of the ITT population produced consistent
results.

In a recent meta-analysis of pooled individual patient data from a total
of 8710 patients from BONE, MOBILE, DIVA, and the IV fracture prevention
study, Harris et al. evaluated comparisons of annual cumulative exposure
(ACE) of ibandronate on non-vertebral fracture risk.^11^ The high dose
group (ACE of ≥10.8 mg) included 150 mg oral monthly, 2 mg IV every 2
months, and 3 mg IV quarterly dosing regimens. A significant reduction
in non-vertebral fracture risk was noted in the high dose group compared
to placebo (35% relative risk reduction). Individual clinical trials
were not powered to detect significant differences in non-vertebral
fractures. Limitations of this meta-analysis include that fracture rates
were determined from the two placebo-controlled studies; different
dosing regimens were pooled together; and potential differences in study
populations may exist.

*Prevention of Osteoporosis in Postmenopausal Women*

In a randomized, double-blind, multicenter, placebo-controlled trial,
the efficacy of oral daily ibandronate (0.5 mg, 1 mg, or 2.5 mg daily)
was evaluated for the prevention of bone loss in 653 postmenopausal
women with osteopenia and no history of fracture.^12^ After 2 years of
treatment, statistically significant increases in and normalization of
mean lumbar spine and hip BMD from baseline versus placebo were observed
in the 2.5 mg group (see Table 2 below). In a subanalysis, bone loss was
greater in women who were recently menopausal (within the past 1-3
years) compared with those \>3 years postmenopause.

Table 2. Mean BMD changes from baseline in major clinical trials

  ------------------------------ --------------------- -------------------
  **Study/Intervention**         **Lumbar Spine BMD**  **Total Hip BMD**

  **BONE** (3 yr)                                      

  2.5 mg PO daily                +6.5%\*               +3.4%\*

  20 mg PO intermittent          +5.7%\*               +2.9%\*

  Placebo                        +1.3%                 -0.7%

  **MOBILE** (2 yr                                     
  non-inferiority)                                     

  2.5 mg PO daily                +5%                   +2.5%

  50+50 mg PO monthly            +5.3%                 +2.8%

  100 mg PO monthly              +5.6%                 +3.5%\*\*

  150 mg PO monthly              +6.6%\*\*             +4.2%\*\*

  **DIVA** (1 yr results --                            
  non-inferiority)                                     

  2.5 mg PO daily                +3.8%                 +1.8%

  2 mg IV q2 months              +5.1%\*\*             +2.6%\*\*

  3 mg IV q3 months              +4.8%\*\*             +2.4%\*\*

  **Prevention** (2 yr)                                

  0.5 mg PO daily                -0.5%                 -0.5%

  1 mg PO daily                  +0.3%\*               0

  2.5 mg PO daily                +1.9%\*               +1.2%\*

  Placebo                        -1.2%                 -0.6%
  ------------------------------ --------------------- -------------------

\*significant vs. placebo

\*\*significant vs. active control (daily regimen)

*Osteoporosis in Men*

Evidence for the effectiveness of ibandronate in males is limited to a
prospective, open-label pilot study that evaluated change in lumbar
spine BMD in 14 men with a baseline osteoporotic fracture.^1,13^
Patients received 2 mg IV ibandronate every 3 months. After two years,
significant increases in mean lumbar spine and trochanter BMD (6.7% and
3.2% respectively) were observed.

A Phase IV trial sponsored by Roche is planned to evaluate oral
ibandronate monthly in male osteoporosis and is currently recruiting
subjects (Clinical trial identifier NCT00397839).

*Treatment of Glucocorticoid-Induced Osteoporosis*

In an open label, parallel group clinical trial, 2 mg IV ibandronate was
compared to alfacalcidol in 115 patients (53 men and 62 women) with
corticosteroid-induced osteoporosis.^1,14^ After 3 years of treatment,
lumbar spine BMD in ibandronate-treated patients increased by a mean of
13.3% (±7.2) compared with 2.6% (±2.3) increase in alfacalcidol group.
Although not powered to detect a difference, a decreased frequency of
vertebral fractures was noted in the ibandronate group (8.6% vs. 22.8%
in alfacalcidol group).

*Paget's Disease*

Evidence for the effectiveness of ibandronate in the treatment of
Paget's disease is limited. In one study of 20 patients (12 males; 8
females) evaluating the usefulness of novel bone turnover markers,
ibandronate 2 mg IV was given either by injection or by 24 hour
infusion.^15^ As measured by the established marker, serum total
alkaline phosphatase (TAP), 11 of 20 patients achieved normalization of
levels with treatment (\<170 U/L). All patients relapsed (≥25% increase
over nadir) by 12 months. No differences in response were observed
between infusion and injection groups. The authors concluded that 2 mg
IV ibandronate is insufficient to normalize disease activity in most
patients in the treatment of Paget's disease.

A separate report described 2 additional studies: 1) retreatment of 13
patients from the above study with 2 mg IV ibandronate injection and 2)
treatment of 14 patients with high dose ibandronate (4 or 6 mg IV
infusion).^16^ Patients were recruited to the high dose group based on
high levels of TAP and/or failure to normalize with previous treatment
of 2 mg IV ibandronate. In the retreatment study, 6 of 13 patients
achieved normalization of TAP levels, which is similar to the response
observed with the first dose (5 of 13). In the high dose study, 6 of 10
and 2 of 4 patients achieved normalization of TAP levels in the 4 mg and
6 mg groups, respectively. The authors concluded that further study is
needed to determine the optimal dosing regimen for ibandronate.

**Adherence**

Patient adherence to medications including bisphosphonates in the
treatment of osteoporosis is generally poor.^17-19^ Factors that may
negatively influence adherence include absence of symptoms prior to
fracture (and unclear benefit of the medication), inconvenient dosing
instructions, cost, and side effects.^1,20^ Low adherence to
osteoporosis treatment has been linked to higher risk of fracture in
several evaluations utilizing patient populations from large healthcare
database systems.^21-24^ Reduction in overall fracture risk in the range
of approximately 16-30% (although this may vary) has been observed in
patients with high rates of compliance and persistence (approximately
80% or greater) compared to noncompliant patients.

In efforts to improve compliance, extended interval bisphosphonate
dosing regimens have become available including weekly, monthly,
quarterly, and yearly formulations. In evaluations comparing weekly and
daily oral bisphosphonates, weekly bisphosphonates were generally
associated with higher rates of compliance; however, compliance with all
regimens remained suboptimal.^17-19^

Direct comparisons of ibandronate regimens that evaluated preference and
persistence include BALTO, PERSIST, and a study by Gold et al.^25-27^ In
the BALTO trial (n=342), a randomized, 6 month, open-label cross over
trial, 66% of patients cited a preference for monthly ibandronate over
weekly alendronate, most commonly for reasons of convenience. In the
PERSIST trial (n=1103), more patients persisted on monthly ibandronate
along with a patient support program than on weekly alendronate at 6
months of therapy (56.6% vs 38.6%; p \<0.05). Gold et al. showed that
patients are influenced by knowledge of anti-fracture efficacy of
bisphosphonates and preferred weekly risedronate over monthly
ibandronate when informed of the proven non-vertebral anti-fracture
efficacy of risedronate. Limitations with these evaluations include the
short duration and some methodological issues. None investigated the
effects of adherence on outcomes. However, taken as a whole, patients
seem to prefer more convenient regimens, which may lead to improved
adherence and persistence. Additionally, increased knowledge about
medications can influence patient preference and adherence.

# Adverse Events (Safety Data)

Both oral and IV formulations of ibandronate were generally well
tolerated in clinical trials, with adverse events occurring with similar
frequency overall in the treatment and placebo groups. Oral ibandronate
has been studied in \>3900 women with PMO for durations of up to 3
years. Intravenous ibandronate has been studied in \>5000 women with PMO
for durations of up to 3 years.^1-3^

## Serious Adverse Events

Serious adverse events were reported in similar frequencies in all
placebo and treatment groups in the four major clinical trials (BONE,
Prevention, MOBILE, DIVA). Serious adverse events related to drug
therapy occurred rarely (≤1.1% of patients). Eight total serious adverse
events were reported among the safety population of 1583 patients in the
MOBILE trial: gastric ulcer (two patients), duodenal ulcer, erosive
duodenitis, gastric ulcer hemorrhage, hemorrhagic gastritis, melena, and
liver disorder.^8^

^Table\ 3.\ Tolerability\ of\ ibandronate6,8-10^

+--------+------+------+------+------+------+------+------+------+
|        | **BO |      | **   |      | **   |      | **   |      |
|        | NE** |      | Prev |      | MOBI |      | DIVA |      |
|        |      |      | enti |      | LE** |      | (at  |      |
|        |      |      | on** |      |      |      | 1    |      |
|        |      |      |      |      |      |      | y    |      |
|        |      |      |      |      |      |      | r)** |      |
+--------+------+------+------+------+------+------+------+------+
|        | **I  | **P  | **I  | **P  | **I  | **I  | **I  | **I  |
|        | band | lace | band | lace | band | band | band | band |
|        | 2.5  | bo** | 2.5  | bo** | 150  | 2.5  | 3 mg | 2.5  |
|        | mg   |      | mg   |      | mg   | mg   | IV   | mg   |
|        | PO   | **(  | PO   | **(  | PO   | PO   | q3   | PO   |
|        | dai  | n=97 | dai  | n=15 | dai  | dai  | mont | dai  |
|        | ly** | 5)** | ly** | 9)** | ly** | ly** | hs** | ly** |
|        |      |      |      |      |      |      |      |      |
|        | **(  |      | **(  |      | **(  | **(  | **(  | **(  |
|        | n=97 |      | n=16 |      | n=39 | n=39 | n=46 | n=46 |
|        | 7)** |      | 3)** |      | 6)** | 5)** | 9)** | 5)** |
+--------+------+------+------+------+------+------+------+------+
| All    | 329  | 347  | 30   | 27   | 74(  | 70   | 75   | 56   |
| withd  | (    | (    | (    | (    | 19%) | (    | (    | (    |
| rawals | 34%) | 36%) | 18%) | 17%) |      | 18%) | 16%) | 12%) |
+--------+------+------+------+------+------+------+------+------+
| Due to | 175  | 180  | 12   | 14   | 37   | 41   | 41   | 31   |
| AE     | (    | (    | (7%) | (9%) | (9%) | (    | (9%) | (7%) |
|        | 18%) | 19%) |      |      |      | 10%) |      |      |
+--------+------+------+------+------+------+------+------+------+
| Other  | 154  | 167  | 18   | 13   | 37   | 29   | 34   | 25   |
|        | (    | (    | (    | (8%) | (9%) | (7%) | (7%) | (5%) |
|        | 15%) | 17%) | 11%) |      |      |      |      |      |
+--------+------+------+------+------+------+------+------+------+

^Table\ 4.\ Adverse\ events\ (%)\ reported\ in\ ≥2%\ of\ patients\ in\ the\ pivotal\ clinical\ trials1-3^

+--------------+--------+--------+--------+--------+--------+--------+
|              | **BONE |        | **MO   |        | **     |        |
|              | and    |        | BILE** |        | DIVA** |        |
|              | Prev   |        |        |        |        |        |
|              | ention |        |        |        |        |        |
|              | (poo   |        |        |        |        |        |
|              | led)** |        |        |        |        |        |
+--------------+--------+--------+--------+--------+--------+--------+
| **Adverse    | *      | **Pla  | *      | *      | *      | *      |
| Event**      | *Iband | cebo** | *Iband | *Iband | *Iband | *Iband |
|              | 2.5 mg |        | 150 mg | 2.5 mg | 3 mg   | 2.5 mg |
|              | PO     | **(n=1 | PO     | PO     | IV q3  | PO     |
|              | d      | 134)** | d      | d      | mo     | d      |
|              | aily** |        | aily** | aily** | nths** | aily** |
|              |        |        |        |        |        |        |
|              | **(n=1 |        | **(n=  | **(n=  | **(n=  | **(n=  |
|              | 140)** |        | 396)** | 395)** | 469)** | 465)** |
+--------------+--------+--------+--------+--------+--------+--------+
| Abdominal    |        |        | 7.8    | 5.3    | 5.1    | 5.6    |
| pain         |        |        |        |        |        |        |
+--------------+--------+--------+--------+--------+--------+--------+
| Allergic     | 2.5    | 1.9    |        |        |        |        |
| reaction     |        |        |        |        |        |        |
+--------------+--------+--------+--------+--------+--------+--------+
| Arthralgia   |        |        | 5.6    | 3.5    | 9.6    | 8.6    |
+--------------+--------+--------+--------+--------+--------+--------+
| Arthritis    | 3.2    | 2.7    |        |        |        |        |
+--------------+--------+--------+--------+--------+--------+--------+
| Asthenia     | 3.5    | 2.3    |        |        |        |        |
+--------------+--------+--------+--------+--------+--------+--------+
| Back pain    | 13.5   | 12.2   | 4.5    | 4.3    | 7      | 7.5    |
+--------------+--------+--------+--------+--------+--------+--------+
| Bronchitis   | 10     | 6.8    | 2.5    | 3.5    | 2.1    | 2.8    |
+--------------+--------+--------+--------+--------+--------+--------+
| Constipation |        |        | 4      | 2.5    | 3.4    | 4.1    |
+--------------+--------+--------+--------+--------+--------+--------+
| Cystitis     |        |        |        |        | 1.9    | 3.4    |
+--------------+--------+--------+--------+--------+--------+--------+
| Depression   |        |        |        |        | 1.3    | 2.2    |
+--------------+--------+--------+--------+--------+--------+--------+
| Diarrhea     | 6.8    | 5      | 5.1    | 4.1    | 2.8    | 2.4    |
+--------------+--------+--------+--------+--------+--------+--------+
| Dizziness    | 3.7    | 2.6    | 2.3    | 1      | 1.9    | 2.8    |
+--------------+--------+--------+--------+--------+--------+--------+
| Dyspepsia    | 11.9   | 9.8    | 5.6    | 7.1    | 3.6    | 4.3    |
+--------------+--------+--------+--------+--------+--------+--------+
| Fatigue      |        |        |        |        | 2.8    | 1.1    |
+--------------+--------+--------+--------+--------+--------+--------+
| Gas          |        |        |        |        | 1.5    | 3.4    |
| troenteritis |        |        |        |        |        |        |
+--------------+--------+--------+--------+--------+--------+--------+
| Gastritis    | 2.2    | 1.9    |        |        | 1.9    | 2.2    |
+--------------+--------+--------+--------+--------+--------+--------+
| Headache     | 6.5    | 5.8    | 3.3    | 4.1    | 3.6    | 2.6    |
+--------------+--------+--------+--------+--------+--------+--------+
| Hypercho     | 4.8    | 4.2    |        |        | 1.5    | 4.3    |
| lesterolemia |        |        |        |        |        |        |
+--------------+--------+--------+--------+--------+--------+--------+
| Hypertension |        |        | 6.3    | 7.3    | 5.3    | 7.1    |
+--------------+--------+--------+--------+--------+--------+--------+
| Infection    | 4.3    | 3.4    |        |        |        |        |
+--------------+--------+--------+--------+--------+--------+--------+
| Influenza    |        |        | 4      | 3.8    | 4.7    | 8      |
+--------------+--------+--------+--------+--------+--------+--------+
| In           |        |        | 3.3    | 0.8    | 4.9    | 1.1    |
| fluenza-like |        |        |        |        |        |        |
| illness      |        |        |        |        |        |        |
+--------------+--------+--------+--------+--------+--------+--------+
| Insomnia     |        |        | 2      | 0.8    | 1.1    | 2.6    |
+--------------+--------+--------+--------+--------+--------+--------+
| Joint        | 3.6    | 3.3    |        |        |        |        |
| disorder     |        |        |        |        |        |        |
+--------------+--------+--------+--------+--------+--------+--------+
| Localized    |        |        | 3      | 1.3    | 1.5    | 2.4    |
| os           |        |        |        |        |        |        |
| teoarthritis |        |        |        |        |        |        |
+--------------+--------+--------+--------+--------+--------+--------+
| Muscle cramp |        |        | 1.8    | 2      |        |        |
+--------------+--------+--------+--------+--------+--------+--------+
| Myalgia      | 5.7    | 5.1    | 2      | 0.8    | 2.8    | 0.9    |
+--------------+--------+--------+--------+--------+--------+--------+
| Nas          |        |        | 3.5    | 4.3    | 3.4    | 6      |
| opharyngitis |        |        |        |        |        |        |
+--------------+--------+--------+--------+--------+--------+--------+
| Nausea       |        |        | 5.1    | 4.8    | 2.1    | 4.3    |
+--------------+--------+--------+--------+--------+--------+--------+
| Nerve root   | 2.2    | 1.9    |        |        |        |        |
| lesion       |        |        |        |        |        |        |
+--------------+--------+--------+--------+--------+--------+--------+
| Pain in      | 7.8    | 6.4    | 4      | 1.3    | 2.8    | 2.2    |
| extremity    |        |        |        |        |        |        |
+--------------+--------+--------+--------+--------+--------+--------+
| Pharyngitis  | 2.5    | 1.5    |        |        |        |        |
+--------------+--------+--------+--------+--------+--------+--------+
| Pneumonia    | 5.9    | 4.3    |        |        |        |        |
+--------------+--------+--------+--------+--------+--------+--------+
| Rash         |        |        | 2.3    | 1.3    | 2.3    | 2.8    |
+--------------+--------+--------+--------+--------+--------+--------+
| Tooth        | 3.5    | 2.3    |        |        |        |        |
| disorder     |        |        |        |        |        |        |
+--------------+--------+--------+--------+--------+--------+--------+
| Upper        | 33.7   | 33.2   | 2      | 2      | 1.1    | 2.8    |
| respiratory  |        |        |        |        |        |        |
| infection    |        |        |        |        |        |        |
+--------------+--------+--------+--------+--------+--------+--------+
| Urinary      | 5.5    | 4.2    |        |        | 2.6    | 3.2    |
| tract        |        |        |        |        |        |        |
| infection    |        |        |        |        |        |        |
+--------------+--------+--------+--------+--------+--------+--------+
| Vertigo      | 3      | 2.5    |        |        |        |        |
+--------------+--------+--------+--------+--------+--------+--------+

# Precautions/Contraindications^1-3^

## Contraindications

-   Hypersensitivity to ingredients

-   Inability to sit upright or stand for 60 minutes following
    administration of oral tablets

-   Uncorrected hypocalcemia

## Precautions

*Mineral Metabolism*

Small reductions in serum calcium may occur with bisphosphonate therapy,
which are generally not clinically significant unless underlying
deficiencies are present.^28^ Hypocalcemia, vitamin D deficiency, and
other bone and mineral metabolic abnormalities should be corrected prior
to initiating therapy with ibandronate. Transient hypocalcemia may occur
with IV administration of the drug. Patients receiving ibandronate must
have adequate intake of calcium and vitamin D.

*Gastrointestinal Effects*

Oral administration of bisphosphonates as a class is associated with
adverse upper GI events including dysphagia, esophagitis, and esophageal
and gastric ulcers. To minimize the risk of these adverse effects,
patients should adhere to the special dosing administration instructions
(see Dosage and Administration section).

Major clinical trials evaluating ibandronate (BONE, MOBILE, Prevention)
did not specifically exclude patients with GI disorders or those taking
medications with the potential for additive GI irritation (i.e., NSAIDs,
aspirin).^6,8,12,29^ A significant and similar proportion of patients
across treatment groups were taking concomitant NSAIDs (35-37%) and had
pre-existing GI disorders (25-28%) in the BONE trial. Upper GI adverse
events occurred with similar frequency among ibandronate and placebo
groups as well as in the subpopulations on NSAIDs or with pre-existing
GI disorder. In the Prevention study, comparable upper GI events
occurred in ibandronate and placebo groups. Although no differences in
overall reports of adverse GI events were observed, an evenly
distributed but higher proportion of patients with a history of GI
disorders or on concomitant NSAIDs reported adverse events in the MOBILE
trial. In summary, unique safety concerns with ibandronate regarding GI
effects have not been identified. No apparent differences in GI
tolerance in daily versus monthly oral ibandronate regimens have been
observed. Caution should be exercised with ibandronate as with other
bisphosphonates, as upper GI disorders may occur with treatment.

*Osteonecrosis of the Jaw (ONJ)*

ONJ has been reported rarely in patients treated with bisphosphonates.
The majority of cases reported have been in patients with cancer treated
with IV bisphosphonates and undergoing dental procedures, although cases
in patients with osteoporosis on oral bisphosphonates have occurred.
Certain pre-existing conditions including cancer, anemia, coagulopathy,
infection, and pre-existing dental disease and concomitant therapy with
chemo, radiation, or corticosteroids are known risk factors. In a recent
review of ONJ in patients with osteoporosis treated with oral
bisphosphonates, 26 total cases in the literature were reported.^30^
Characteristics of these patients included age ≥60 years, female, and
history of invasive dental treatment. Whether discontinuing
bisphosphonate therapy and for how long prior to an invasive dental
procedure reduces the risk of ONJ is unknown.

*Musculoskeletal Pain*

Severe and sometimes incapacitating musculoskeletal pain has been
reported in patients taking bisphosphonates, including ibandronate. The
FDA recently issued a letter for healthcare professionals to aid in
recognition of bisphosphonates as a possible cause in patients
presenting with these symptoms.^31^ According to a postmarketing review,
symptoms may occur within days to years of initiating therapy. Symptoms
resolve quickly and completely in many patients after discontinuing the
bisphosphonate, although recovery may be slow and partial in others.
Risk factors and incidence are unknown.

*Pregnancy/Lactation*

Ibandronate belongs to FDA Pregnancy Category C. There are no well
controlled studies of ibandronate in pregnant women, although fetal harm
has been demonstrated in animal studies. Ibandronate should only be used
during pregnancy when the benefits justify the potential risks. It is
not known whether ibandronate is excreted in human milk. Caution should
be exercised if ibandronate is prescribed to a breastfeeding mother.

*Renal Impairment*

Intravenous administration of bisphosphonates has been associated with
renal impairment and rarely, acute renal failure. No cases of renal
failure were reported in the clinical development program with
ibandronate. Monitoring of serum creatinine prior to each dose of IV
ibandronate therapy is recommended. Therapy should be withheld in the
presence of worsening renal function. Close monitoring is recommended in
patients with pre-existing conditions or on medications that may
predispose them to renal impairment.

*Atrial Fibrillation*

Recent findings from a clinical efficacy trial with zoledronic acid as
well as a retrospective review of a previously completed trial with
alendronate have identified a potential association of bisphosphonates
and atrial fibrillation.^32-34^ At this time, it is unclear whether
there is a true association and whether it may be a class effect.

# 

# 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:

+-----------------+----------------------------------------------------+
| **Drug Name**   | **LA/SA Drug Name**                                |
+-----------------+----------------------------------------------------+
| **Ibandronate   | Alendronate 10 mg tablets                          |
| (generic)**     |                                                    |
|                 |                                                    |
| **2.5 mg        |                                                    |
| tablets, 150 mg |                                                    |
| tablets, 1      |                                                    |
| mg/ml 3 ml      |                                                    |
| injection**     |                                                    |
+-----------------+----------------------------------------------------+
|                 | Etidronate 50 mg/ml injection                      |
+-----------------+----------------------------------------------------+
|                 | Nilandron\* 150 mg tablet                          |
+-----------------+----------------------------------------------------+
|                 | Pamidronate 3 mg/ml injection                      |
+-----------------+----------------------------------------------------+
|                 | Risedronate 30 mg tablets                          |
+-----------------+----------------------------------------------------+
| **Boniva        | Januvia 25 mg tablets                              |
| (brand)**       |                                                    |
|                 |                                                    |
| **2.5 mg        |                                                    |
| tablets, 150 mg |                                                    |
| tablets, 1      |                                                    |
| mg/ml 3 ml      |                                                    |
| injection**     |                                                    |
+-----------------+----------------------------------------------------+
|                 | Kariva 0.15 mg tablets                             |
+-----------------+----------------------------------------------------+
|                 | Levitra 2.5 mg tablets                             |
+-----------------+----------------------------------------------------+
|                 | Tarceva 150 mg tablets                             |
+-----------------+----------------------------------------------------+
|                 | Univasc 15 mg tablets                              |
+-----------------+----------------------------------------------------+

\*Identified as a High Alert Medication per ISMP (i.e., special
precautions must be taken in the receipt, storage, distribution and
administration of these drugs)

# Drug Interactions^1-3^

## Drug Interactions

Ibandronate is not metabolized by the liver and is not an inhibitor of
the cytochrome P450 system. Renally eliminated, ibandronate does not
interfere with known acidic or basic transport systems involved in the
excretion of other drugs based on animal studies.

*Calcium and Multivalent Cations*

Concomitant oral administration of medications or supplements containing
multivalent cations (i.e., calcium, aluminum, magnesium, and iron) is
likely to interfere with oral ibandronate absorption. Oral medications
or supplements containing multivalent cations should be taken at least
60 minutes following oral ibandronate.

*Food and Beverages*

Food and beverages other than plain water are known to decrease the
bioavailability of oral ibandronate and should not be consumed less than
60 minutes following oral ibandronate administration.

*Aspirin and Non-Steroidal Anti-inflammatory Drugs (NSAIDs)*

A significant proportion of patients in the major clinical trials with
ibandronate were taking aspirin and/or NSAIDs. The incidence of upper GI
adverse events reported in clinical trials was similar between study
groups (i.e., placebo, daily, and monthly ibandronate). Caution should
be exercised when ibandronate is administered concomitantly with
aspirin/NSAIDs, as all are known to cause GI irritation.

*Other Medications*

No clinically relevant interactions with ibandronate were observed
during pharmacokinetic studies with ranitidine, tamoxifen, melphalan,
and prednisolone.

# Acquisition Costs

Table 5. Ibandronate Acquisition Costs

  ---------------------------- --------------- ------------------------ -----------------------
  **Dose/Regimen**             **Cost/Dose**   **Cost/Patient/Month**   **Cost/Patient/Year**

  Ibandronate 2.5 mg tablets   \$1.58          \$47.25                  \$567.00
  (daily)                                                               

  Ibandronate 150 mg tablets   \$45.41         \$45.41                  \$544.92
  (monthly)                                                             

  Ibandronate 3 mg/3 ml IV     \$299.80        \~\$99.93                \$1199.20
  injection (q3 months)                                                 
  ---------------------------- --------------- ------------------------ -----------------------

Table 6. Comparator Acquisition Costs

  ---------------------------- --------------- ------------------------ -----------------------
  **Drug/Regimen**             **Cost/Dose**   **Cost/Patient/Month**   **Cost/Patient/Year**

  Alendronate 10 mg tablets    \$0.74          \$22.20                  \$266.40
  (daily)                                                               

  Alendronate 70 mg tablets    \$5.15 - \$5.30 \$20.60 - \$21.12        \$247.20 - \$254.40
  (weekly)                                                              

  Risedronate 5 mg tablets     \$1.16          \$34.80                  \$417.60
  (daily)                                                               

  Risedronate 35 mg tablets    \$8.11          \$32.44                  \$389.28
  (weekly)                                                              

  Zoledronic acid 5 mg/100 ml  \$774.90        \$64.58                  \$774.90
  IV infusion (yearly)                                                  
  ---------------------------- --------------- ------------------------ -----------------------

# Conclusions

Ibandronate is a bisphosphonate agent available in oral daily, oral
monthly, and injectable quarterly regimens. Daily oral ibandronate (2.5
mg) has been shown to be superior to placebo in improving vertebral
fracture risk and spine and hip BMD in PMO. No difference in
nonvertebral fracture risk has been proven in individual clinical
trials, although pooled data suggests a benefit with higher doses of
ibandronate (150 mg oral monthly, 3 mg IV quarterly). Extended regimens
(150 mg PO monthly and 3 mg IV quarterly) have been shown to be at least
as effective as the daily regimen in improving spine and hip BMD.
However, decrease in fracture risk (vertebral or non-vertebral) has not
been directly demonstrated with ibandronate extended interval regimens.
Ibandronate is generally well tolerated, and its side effect profile,
including upper GI effects and musculoskeletal symptoms appears similar
to other bisphosphonates. No unique safety concerns with ibandronate
have been identified. Little is known about the safety and effectiveness
of ibandronate in the male population.

Extended interval bisphosphonate regimens including monthly oral and
quarterly injectable ibandronate have become available in attempts to
increase convenience and tolerability, improve adherence and
persistence, and optimally improve outcomes in osteoporosis treatment.
Preliminary study suggests that patients may prefer monthly oral
ibandronate over a weekly oral bisphosphonate regimen; however, it is
not known whether patient preference will translate into improved
outcomes with ibandronate.

**[Recommendations/Place in Therapy]{.underline}**

Potential advantages of ibandronate over other bisphosphonate agents
include the convenience of a monthly or quarterly regimen and the
ability to administer the IV formulation as a bolus rather than
infusion. Potential disadvantages include the lack of efficacy and
safety in males and in other indications (i.e., corticosteroid induced
osteoporosis, Paget's disease). Additionally, the monthly and IV
regimens have not been directly shown to reduce vertebral fractures.
There is no comparative efficacy or safety data available with
ibandronate vs. other bisphosphonates. The cost of ibandronate is higher
than that of alternatives.

# References:

1\. Boniva® Formulary Dossier. Final Version 3.0. Roche Pharmaceuticals.
Nutley NJ. February 2006.

2\. Boniva® Tablets Product Information. Roche Pharmaceuticals. Nutley
NJ. Aug 2006.

3\. Boniva® Injection Product Information. Roche Pharmaceuticals. Nutley
NJ. Feb 2007.

4\. Rosen HN, Drezner MK. Diagnosis and evaluation of osteoporosis in
postmenopausal women. UpToDate.Version 15.3;August 2007.

5\. Small RE. Uses and limitations of bone mineral density measurements
in the management of osteoporosis. Medscape General
Medicine;2005:7(2):3.

6\. Chesnut CH, Skag A, Christiansen C, et al. Effects of oral
ibandronate administered daily or intermittently on fracture risk in
postmenopausal osteoporosis. (BONE) J Bone Miner Res. 2004;19:1241-1249.

7\. Miller PD, McClung MR, MAcovei L, et al. Monthly oral ibandronate
therapy in postmenopausal osteoporosis: 1-year results from the MOBILE
study. J Bone Miner Res. 2005;20:1315-22.

8\. Reginster JY, Adami S, Lakatos P, et al. Efficacy and tolerability
of once-monthly oral ibandronate in postmenopausal osteoporosis: 2 year
results from the MOBILE study. Ann Rheum Dis. 2006;65:654-61.

9\. Delmas PD, Adami S, Strugala C, et al. Intravenous ibandronate
injections in postmenopausal women with osteoporosis: one-year results
from the Dosing Intravenous Administration Study (DIVA). Arthritis
Rheum. 2006;54(6):1838-46.

10\. Recker R, Stakkestad JA, Chesnut CH, et al. Insufficiently dosed
intravenous ibandronate injections are associated with suboptimal
antifracture efficacy in postmenopausal osteoporosis. Bone.
2004;34:890-99.

11\. Harris ST, Blumentals WA, Miller PD. Inbandronate and the risk of
non-vertebral and clinical fractures in women with postmenopausal
osteoporosis: results of a meta-analysis of phase III studies. Curr Med
Res Opin. 2008;24(1):237-45.

12\. McClung MR, Wasnich RD, Recker R, et al. Oral daily ibandronate
prevents bone loss in early postmenopausal women without osteoporosis. J
Bone Min Res. 2004;29(1):11-18.

13\. Lamy O, Sandini L, Pache I, et al. Intravenous ibandronate in men
with osteoporosis: an open pilot study over 2 years. J Endocrinol
Invest. 2003;26(8):728-32.

14\. Ringe JD, Dorst A, Faber H, et al. Intermittent intravenous
ibandronate injections reduce vertebral fracture risk in
corticosteroid-induced osteoporosis: results from a long term
comparative study. Osteoporos Int. 2003;14:801-7.

15\. Woitge HW, Oberwittler H, Heichel S, et al. Short and long term
effects of ibandronate treatment on bone turnover in Paget disease of
the bone. Clin Chem. 2000;46(5):684-90.

16\. Grauer A, Heichel S, Knaus J, et al. Ibandronate treatment in
Paget's disease of the bone. Bone. 1999;24(5 Suppl):87S-89S.

17\. Cramer JA, Amonkar MM, Hebborn A, et al. Compliance and persistence
with bisphosphonate dosing regimens among women with postmenopausal
osteoporosis. Curr Med Res Opin. 2005;21(9):1453-60.

18\. Cramer JA, Gold DT, Silverman SL, et al. A systematic review of
persistence and compliance with bisphosphonates for osteoporosis.
Osteoporos Int. 2007;18:1023-31.

19\. Recker RR, Gallagher R, MacCosbe PE. Effect of dosing frequency on
bisphosphonate medication adherence in a large longitudinal cohort of
women. Mayo Clin Proc. 2005;80(7):856-61.

20\. Osterberg L and Blaschke T. Adherence to medication. N Engl J Med.
2005;353:487-97.

21\. Caro JJ, Ishak KJ, Huybrechts KF, et al. The impact of compliance
with osteoporosis therapy on fracture rates in actual practice.
Osteoporos Int. 2004;15:1003-8.

22\. Rabenda V, Mertens R, Fabri V, et al. Adherence to bisphosphonates
therapy and hip fracture risk in osteoporotic women. Osteoporos Int.
2007; (epub Nov 13).

23\. Siris ES, Harris ST, Rosen CJ, et al. Adherence to bisphosphonate
therapy and fracture rates in osteoporotic women: relationship to
vertebral and nonvertebral fractures from 2 US claims databases. Mayo
Clin Proc. 2006;81(8):1013-1022.

24\. Weycker D, Macarios D, Edelsberg J, et al. Compliance with
osteoporosis drug therapy and risk of fracture. Osteoporos Int.
2007;18:271-7.

25\. Emkey R, Koltun W, Beusterien K, et al. Patient preference for
once-monthly ibandronate versus once-weekly alendronate in a randomized,
open-label, cross-over trial: the Boniva Alendronate Trial in
Osteoporosis (BALTO). Curr Med Res Opin. 2005;21(12):1895-1903.

26\. Cooper A, Drake J, Brankin E. Treatment persistence with
once-monthly ibandronate and patient support vs. once-weekly
alendronate: results from the PERSIST study. Int J Clin Pract.
2006;896-905.

27\. Gold et al. Patient preference and adherence: comparative US
studies between two bisphosphonates, weekly risedronate and monthly
ibandronate. Curr Med Res Opin. 2006;22(12):2383-91.

28\. Rosen HN. Pharmacology of bisphosphonates. UpToDate.Version
15.3;August 2007.

29\. Epstein S, Delmas PD, Emkey R, et al. Oral ibandronate in the
management of postmenopausal osteoporosis: review of upper
gastrointestinal safety. Maturitas.2006;54:1-10.

30\. Pazianas M, Miller P, Blumentals W, et al. A review of the
literature on osteonecrosis of the jaw in patients with osteoporosis
treated with oral bisphosphonates: prevalence, risk factors, and
clinical characteristics. Clin Ther. 2007;29:1548-58.

31\. FDA MedWatch. Bisphosphonates. Information for Healthcare
Professionals. Issued Jan 7, 2008. Available at:
www.fda.gov/cder/drug/InfoSheets/HCP/bisphosphonatesHCP.htm. Accessed
January 7, 2008.

32\. FDA MedWatch. Bisphosphonates. Early communication of an ongoing
safety review. Issued on October 1, 2007, updated January 7, 2008.
Available at: www.fda.gov/cder/drug/early_comm/bisphosphonates.htm.
Accessed January 15, 2008.

33\. Black DM, Delmas PD, Eastel R, et al. Once-yearly zoledronic acid
for treatment of postmenopausal osteoporosis. N Engl J Med.
2007;356:1809-22.

34\. Cummings SR, Schwartz AV, Black DM. Alendronate and atrial
fibrillation. N Engl J Med. 2007;356:18:1895-6. Letter.

**Prepared January 2008. Contact person: Lisa Longo, PharmD, BCPS**

Appendix 1. Ibandronate Clinical Trials

+------+----------+-----------+----------------------------------------+
| *    | **Eli    | **Interv  | **Results**                            |
| *Stu | gibility | entions** |                                        |
| dy** | Cr       |           |                                        |
|      | iteria** |           |                                        |
+======+==========+===========+========================================+
| BONE | **[I     | Ib        | **[Baseline                            |
| S    | nclusion | andronate | demographics]{.underline}** (mean):    |
| tudy | ]{.under | 2.5 mg PO | age 69yrs; ht 160cm; wt 67kg; yrs      |
|      | line}:** | daily     | since menopause 21; patients with 1    |
| Che  |          |           | fracture 93-94%; patients with 2       |
| snut | Female   | Ib        | fractures 42-44%; LS BMD T score -2.7  |
| 2004 |          | andronate | to -2.8; TH BMD T score -1.7; all      |
|      | 55-80    | 20 mg PO  | similar between groups.                |
| R,   | yrs old  | int       |                                        |
| MC,  |          | ermittent |   --------------- -----------          |
| DB,  | ≥5 yrs   | (20 mg    | ---- ------------------ -------------- |
| PC,  | postme   | QOD x12   |                   **DAILY*             |
| PG   | nopause; | doses q3  | *       **INTERMITTENT**   **PLACEBO** |
|      |          | mos)      |                                        |
| n    | 1-4      |           |   ITT (n=2929)                         |
| ~R~= | baseline | Placebo   | 977             977                975 |
| 2946 | v        |           |                                        |
|      | ertebral |           |   Completed       66% (n=6             |
| ITT= | f        |           | 48)     68% (n=662)        64% (n=628) |
| 2929 | ractures |           |   treatment                            |
|      |          |           |                                        |
| PP=  | LS BMD   |           |                                        |
| 2125 | T-score  |           |   Primary                              |
|      | -2 to -5 |           |                                        |
| 3    | in ≥1    |           |   Endpoint                             |
| yrs  | vertebra |           |                                        |
| dura |          |           |                                        |
| tion | **[E     |           |   Morphometric    4                    |
|      | xclusion |           | .7%\*          4.9%\* \[3.4-6.4\] 9.6% |
| Si   | ]{.under |           |   vertebral       \[3.2-6.2            |
| tes: | line}:** |           | \]                        \[7.5-11.7\] |
| N    |          |           |   fracture rate                        |
| orth | LS BMD   |           |                                        |
| Ame  | T-score  |           |                                        |
| rica | \< -5    |           |   RRR                                  |
| and  |          |           |    62%\* \[41-75\] 50%\* \[26-66\]     |
| Eu   | \>2      |           |                                        |
| rope | baseline |           |   Secondary                            |
|      | LS       |           |                                        |
|      | f        |           |   Endpoints                            |
|      | ractures |           |                                        |
|      |          |           |                                        |
|      | Disorder |           |   Clinical        2                    |
|      | or       |           | .8%\*          2.8%\* \[1.6-3.9\] 5.3% |
|      | therapy  |           |   vertebral       \[1.6-3.             |
|      | (within  |           | 9\]                        \[3.7-6.9\] |
|      | the last |           |   fracture rate                        |
|      | 6 mos)   |           |                                        |
|      | known to |           |                                        |
|      | affect   |           |   Clinical        9                    |
|      | bone     |           | .1%            8.9%               8.2% |
|      | me       |           |   osteoporotic                         |
|      | tabolism |           |                                        |
|      |          |           |   non-vertebral                        |
|      | Previous |           |                                        |
|      | t        |           |   fracture rate                        |
|      | reatment |           |                                        |
|      | with     |           |                                        |
|      | bisphos  |           |   LS BMD changes  6                    |
|      | phonates |           | .5%\*          5.7%\*             1.3% |
|      |          |           |   (mean)                               |
|      | Fluoride |           |                                        |
|      | t        |           |                                        |
|      | reatment |           |   TH BMD changes  3.                   |
|      | in past  |           | 4%\*          2.9%\*             -0.7% |
|      | 12 mos   |           |   (mean)                               |
|      | or \>2   |           |                                        |
|      | yrs      |           |                                        |
|      | duration |           |   Height loss                          |
|      |          |           | 3.9             4.7                5.6 |
|      | Renal    |           |   (mm)                                 |
|      | im       |           |                                        |
|      | pairment |           |                                        |
|      | (Cr      |           |   Bone turnover                        |
|      | \>2.4    |           |    Significant,                        |
|      | mg/dL)   |           |   biomarkers                           |
|      |          |           |    sustained                           |
|      | Hy       |           |                                        |
|      | per/hypo |           |    reductions in                       |
|      | calcemia |           |                                        |
|      |          |           |    markers in                          |
|      |          |           |                                        |
|      |          |           |    subpopulation                       |
|      |          |           |                                        |
|      |          |           |    studied                             |
|      |          |           |   --------------- -----------          |
|      |          |           | ---- ------------------ -------------- |
|      |          |           |                                        |
|      |          |           | \*significant vs. placebo; \[95% CI\]  |
|      |          |           |                                        |
|      |          |           | **AE Withdrawals:** 18.5%/18.5%/18.8%  |
|      |          |           | (daily/intermittent/placebo)           |
|      |          |           |                                        |
|      |          |           | **AEs/Safety:** No significant         |
|      |          |           | differences in AEs between groups      |
|      |          |           | including GI events, serious events or |
|      |          |           | deaths                                 |
|      |          |           |                                        |
|      |          |           | **AEs reported in ≥10% patients in any |
|      |          |           | group:** upper respiratory infection,  |
|      |          |           | accidental injury, back pain,          |
|      |          |           | arthralgia, dyspepsia, bronchitis,     |
|      |          |           | osteoporosis fracture                  |
+------+----------+-----------+----------------------------------------+
| MO   | **[I     | Ib        | **[Baseline                            |
| BILE | nclusion | andronate | demographics]{.underline}** (mean):    |
| S    | ]{.under | 2.5 mg PO | age 66 yrs; ht 157-158 cm; wt 64 kg;   |
| tudy | line}:** | daily     | BMI 26 kg/m^2^; yrs since menopause    |
|      |          |           | 18-19; history of fracture 46-49%; LS  |
| Mi   | Female   | Ib        | BMD T score -3.3; all similar between  |
| ller |          | andronate | groups                                 |
| PD   | 55-80    | 50 mg PO  |                                        |
| 2    | yrs old  | daily x2  |   ----------- -------------- --------- |
| 005; |          | monthly   | ---- ------------- ------------------- |
|      | ≥5 yrs   |           |               **DAILY**      **50/     |
| R    | postm    | Ib        | 50       **100         **150 MONTHLY** |
| egin | enopause | andronate |                                        |
| ster |          | 100 mg PO |           MONTHLY**     MONTHLY**      |
| JY   | Oste     | once      |                                        |
| 2    | oporosis | monthly   |   PP (n=1277) 292                      |
| 006; | dx: LS   |           |        291           277           289 |
| Iba  | BMD T    | Ib        |                                        |
| ndro | score    | andronate |   Completed   82% (n=325)    8         |
| nate | (mean)   | 150 mg PO | 3% (n=328)   80% (n=316)   81% (n=322) |
| Dos  | -2 to -5 | once      |   treatment                            |
| sier |          | monthly   |                                        |
| 2006 | **[E     |           |                                        |
|      | xclusion | (all      |   Primary                              |
| R,   | ]{.under | patients  |                                        |
| MC,  | line}:** | received  |   Endpoint                             |
| DB,  |          | calcium   |                                        |
| PG   | PUD      | and       |                                        |
|      | (unco    | vitamin D |   LS BMD      5% \[4.4-5.5\] 5.3%\*    |
| no   | ntrolled | supplem   |        5.6%\*        6.6%\*\^\[6-7.1\] |
| ninf | active   | entation) |   changes                              |
| erio | or       |           |           \[4.8-5.9\]   \[5.1-6.1\]    |
| rity | re       |           |   (mean)                               |
|      | current) |           |                                        |
| n    |          |           |                                        |
| ~R~= | Disorder |           |   Secondary                            |
| 1609 | or       |           |                                        |
|      | therapy  |           |   Endpoints                            |
| PP=  | (within  |           |                                        |
| 1277 | the last |           |                                        |
|      | 6 mos)   |           |   TH BMD      2.5%                     |
| ITT= | known to |           |   2.8%\*        3.5%\*\^      4.2%\*\^ |
| 1572 | affect   |           |   changes                              |
|      | bone     |           |                                        |
| 2    | me       |           |   (mean)                               |
| yrs  | tabolism |           |                                        |
| dura |          |           |                                        |
| tion | Previous |           |   Serum CTx   Signi                    |
|      | t        |           | ficant,                                |
| Si   | reatment |           |               susta                    |
| tes: | with     |           | ined                                   |
| N    | bisphos  |           |               reduc                    |
| orth | phonates |           | tions in                               |
| Amer |          |           |               all g                    |
| ica, | Fluoride |           | roups                                  |
| Eur  | t        |           |   ----------- -------------- --------- |
| ope, | reatment |           | ---- ------------- ------------------- |
| Au   | in past  |           |                                        |
| stra | 12 mos   |           | \*noninferior to daily regimen; \^p    |
| lia, | or \>2   |           | \<0.05 vs. daily regimen; \[95% CI\];  |
| S    | yrs      |           | sCTx= C-telopeptide of the alpha-chain |
| outh | duration |           | of type I collagen                     |
| Af   |          |           |                                        |
| rica | Renal    |           | **AE Withdrawals:** 10%/8%/11%/9%      |
|      | im       |           | (daily/50-50/100/150)                  |
|      | pairment |           |                                        |
|      | (Cr      |           | **Clinical Osteoporotic Fractures:**   |
|      | \>2.4    |           | 6.1%/7.3%/6.1%/6.8%                    |
|      | mg/dL)   |           | (daily/50-50/100/150)                  |
|      |          |           |                                        |
|      | CI to    |           | **AEs occurring more frequently in     |
|      | calcium  |           | monthly groups than daily group:**     |
|      | or       |           | arthralgia, dizziness, myalgia,        |
|      | vitamin  |           | flu-like illness                       |
|      | D        |           |                                        |
+------+----------+-----------+----------------------------------------+
| DIVA | **[I     | Ib        | **[Baseline                            |
| S    | nclusion | andronate | Demographics]{.underline}** (mean):    |
| tudy | ]{.under | 2.5 mg PO | age 66 yrs; ht 158 cm; wt 63-64 kg;    |
|      | line}:** | daily     | BMI 25-26 kg/m^2^; yrs since menopause |
| De   |          |           | 18-19; LS BMD T score -3.3; baseline   |
| lmas | Female   | Ib        | fracture 42-44%; all similar between   |
| PD   |          | andronate | groups                                 |
| 2    | 55-80    | 2 mg IV   |                                        |
| 006; | yrs old  | q2 mos    |   ------------ ------------- -         |
|      |          |           | -------------------- ----------------- |
| Iba  | ≥5 yrs   | Ib        |                **2.5 MG PO   *         |
| ndro | postm    | andronate | *2MG IV Q2 MOS**     **3MG IV Q3 MOS** |
| nate | enopause | 3 mg IV   |                                        |
| Dos  |          | q3 mos    |   DAILY**                              |
| sier | Oste     |           |                                        |
| 2006 | oporosis | (all      |   PP (n=1104)  3                       |
|      | dx: LS   | patients  | 81           355                   368 |
| R,   | BMD T    | received  |                                        |
| MC,  | score    | 500 mg    |   Completed 1  87% (n=40               |
| DB,  | (mean)   | oral      | 9)   84% (n=382)           84% (n=394) |
| PG,  | -2 to -5 | calcium   |   yr of                                |
| no   |          | and 400   |                                        |
| ninf | **[E     | iu oral   |   treatment                            |
| erio | xclusion | vitamin D |                                        |
| rity | ]{.under | daily     |                                        |
|      | line}:** | supplem   |   Primary                              |
| n    |          | entation) |                                        |
| ~R~= | Previous |           |   Endpoint                             |
| 1395 | IV       |           |                                        |
|      | bispho   |           |                                        |
| PP=  | sphonate |           |   LS BMD       3.                      |
| 1104 | therapy  |           | 8%          5.1%\*\^\[4.7-5.5\]   4.8% |
|      |          |           |   changes      \[3.4-4.2\]             |
| 2    | Therapy  |           |                        \*\^\[4.5-5.2\] |
| yrs  | within   |           |   (mean)^†^                            |
| dura | the last |           |                                        |
| tion | 6 mos    |           |                                        |
| (1   | known to |           |   Secondary                            |
| yr   | affect   |           |                                        |
| data | bone     |           |   Endpoints                            |
| av   | me       |           |                                        |
| aila | tabolism |           |                                        |
| ble) | (i       |           |   TH BMD       1.8%                    |
|      | ncluding |           |         2.6%\*\^              2.4%\*\^ |
| Si   | bisphosp |           |   changes                              |
| tes: | honates) |           |                                        |
| N    |          |           |   (mean)                               |
| orth | Renal    |           |                                        |
| Amer | im       |           |                                        |
| ica, | pairment |           |   Serum CTx                            |
| Eur  | (Cr      |           |   Significant                          |
| ope, | \>2.4    |           |                                        |
| Au   | mg/dL)   |           |   reductions in                        |
| stra |          |           |                                        |
| lia, | History  |           |   all groups                           |
| S    | of major |           |   ------------ ------------- -         |
| outh | upper GI |           | -------------------- ----------------- |
| Af   | disease  |           |                                        |
| rica |          |           | ^†^n=377/353/365 for LS BMD at 1 yr    |
|      | Allergy  |           | (daily/2mgIV /3mgIV); \*noninferior to |
|      | to       |           | daily regimen; \^p \<0.05 vs. daily    |
|      | bisphos  |           | regimen; \[95% CI\]; sCTx=             |
|      | phonates |           | C-telopeptide of the alpha-chain of    |
|      |          |           | type I collagen                        |
|      |          |           |                                        |
|      |          |           | **AE Withdrawals:** 4.5%/5.4%/6.6%     |
|      |          |           | (2.5PO/2IV/3IV)                        |
|      |          |           |                                        |
|      |          |           | **Clinical fractures:** 17/13/13       |
|      |          |           | (2.5PO/2IV/3IV)                        |
|      |          |           |                                        |
|      |          |           | **Renal AEs:** 2%/3%/2%                |
|      |          |           | (2.5PO/2IV/3IV)                        |
|      |          |           |                                        |
|      |          |           | **Flu-like symptoms:** 1.1%/5.1%/4.9%  |
|      |          |           | (2.5PO/2IV/3IV)                        |
|      |          |           |                                        |
|      |          |           | **Common AEs:** dyspepsia, upper       |
|      |          |           | abdominal pain, arthralgia, and        |
|      |          |           | flu-like illness                       |
+------+----------+-----------+----------------------------------------+
| Re   | **[I     | Ib        | **[Baseline                            |
| cker | nclusion | andronate | demographics]{.underline}** (mean):    |
| R    | ]{.under | 0.5 mg IV | age 67 yrs; LS BMD T score -2.7 to     |
| 2    | line}:** | q3 mos    | -2.79; TH BMD T score -1.8 to -1.9; 1  |
| 004; |          |           | baseline vertebral fracture 48-51%;    |
| Dos  | Female   | Ib        | \>1 baseline vertebral fracture 47-50% |
| sier |          | andronate | ; all similar between groups           |
| 2006 | 55-76    | 1 mg IV   |                                        |
|      | yrs old  | q3 mos    |   -------------- ---                   |
| R,   |          |           | ---------- ------------- ------------- |
| DB,  | ≥5 yrs   | Placebo   |                  *                     |
| PG   | postme   |           | *0.5MG IV q3 **1MG IV q3   **PLACEBO** |
|      | nopause; | (all      |                                        |
| n    |          | patients  |           MOS**         MOS**          |
| ~R~= | 1-4      | received  |                                        |
| 2862 | baseline | 500 mg    |   ITT (n=2                             |
|      | v        | oral      | 860)   950           961           949 |
| ITT= | ertebral | calcium   |                                        |
| 2860 | f        | and 400   |   Completed      8                     |
|      | ractures | iu oral   | 4% (n=798)   80% (n=774)   83% (n=787) |
| 3    |          | vitamin D |   treat                                |
| yrs  | LS BMD   | daily     | ment                                   |
| dura | T-score  | supplem   |                                        |
| tion | -2 to -5 | entation) |   Prima                                |
|      | in ≥1    |           | ry                                     |
|      | vertebra |           |   Endpo                                |
|      |          |           | int                                    |
|      | **[E     |           |                                        |
|      | xclusion |           |   Morphometr                           |
|      | ]{.under |           | ic   8.7%          9.2%          10.7% |
|      | line}:** |           |   verte                                |
|      |          |           | bral                                   |
|      | Disorder |           |   fract                                |
|      | or       |           | ure rate                               |
|      | therapy  |           |                                        |
|      | (within  |           |   Secon                                |
|      | the last |           | dary                                   |
|      | 6 mos)   |           |   Endpo                                |
|      | known to |           | ints                                   |
|      | affect   |           |                                        |
|      | bone     |           |   Clinical                             |
|      | me       |           |      10.2%         10.8%         12.6% |
|      | tabolism |           |   osteo                                |
|      |          |           | porotic                                |
|      | Previous |           |   fract                                |
|      | t        |           | ures                                   |
|      | reatment |           |                                        |
|      | with     |           |   LS BMD changes                       |
|      | bisphos  |           |  3.9%          4.9%          not given |
|      | phonates |           |   (mean                                |
|      |          |           | )         \[3.6-4.3\]   \[4.6-5.3\]    |
|      | T        |           |                                        |
|      | reatment |           |   TH BMD changes                       |
|      | with     |           |  1.1%          2.3%          not given |
|      | investi  |           |   (mean                                |
|      | gational |           | )         \[0.8-1.3\]   \[2-2.6\]      |
|      | drug in  |           |   -------------- ---                   |
|      | past 30  |           | ---------- ------------- ------------- |
|      | days     |           |                                        |
|      |          |           | \*significant vs. placebo; \[95% CI\]  |
|      | Fluoride |           |                                        |
|      | t        |           | **AE Withdrawals:** 8%/11%/8%          |
|      | reatment |           | (0.5/1/placebo)                        |
|      | in past  |           |                                        |
|      | 12 mos   |           | **AEs reported in ≥1% higher incidence |
|      | or \>2   |           | in active treatment arms:** myalgia,   |
|      | yrs      |           | sinusitis, headache, joint disorder,   |
|      | duration |           | asthenia, injection site reaction      |
|      |          |           |                                        |
|      | Renal    |           |                                        |
|      | im       |           |                                        |
|      | pairment |           |                                        |
|      | (Cr      |           |                                        |
|      | \>2.4    |           |                                        |
|      | mg/dL)   |           |                                        |
|      |          |           |                                        |
|      | CI to    |           |                                        |
|      | calcium  |           |                                        |
|      | therapy  |           |                                        |
|      |          |           |                                        |
|      | Hy       |           |                                        |
|      | per/hypo |           |                                        |
|      | calcemia |           |                                        |
+------+----------+-----------+----------------------------------------+
| Pr   | **[I     | Ib        | **[Baseline                            |
| even | nclusion | andronate | demographics]{.underline}** (mean):    |
| tion | ]{.under | 0.5 mg PO | 58-59; yrs since menopause 8-9; wt     |
|      | line}:** | daily     | 71-75 kg; LS BMD T score -1 to -1.1;   |
| McC  |          |           | all similar between groups             |
| lung | Female   | Ib        |                                        |
| 2    |          | andronate |   ----------- -----                    |
| 004; | ≥5 yrs   | 1 mg PO   | ---- --------- --------- ------------- |
|      | postme   | daily     |               **0                      |
| Dos  | nopause; |           | .5MG   **1MG     **2.5MG   **PLACEBO** |
| sier |          | Ib        |                                        |
| 2006 | No       | andronate |         DAILY**   DAILY**   DAILY**    |
|      | history  | 2.5 mg PO |                                        |
| R,   | of       | daily     |   Completed   86%                      |
| DB,  | oste     |           |        87%       82%       83% (n=132) |
| MC,  | oporotic | Placebo   |   trea                                 |
| PG   | f        |           | tment   (n=138)   (n=144)   (n=133)    |
|      | ractures | (all      |                                        |
| n~R~ |          | patients  |   LS BMD                               |
| =653 | LS BMD   | received  |    -0.5%     0.3%\*    1.9%\*    -1.2% |
|      | T-score  | 500 mg    |   chan                                 |
| ITT  | \>-2.5   | oral      | ges                                    |
| =620 |          | calcium   |   (mea                                 |
|      | **[E     | supple    | n)                                     |
| 2    | xclusion | mentation |                                        |
| yrs  | ]{.under | daily)    |   TH BMD                               |
| dura | line}:** |           |    -0.5%     0         1.2%\*    -0.6% |
| tion |          |           |   chan                                 |
|      | B        |           | ges                                    |
|      | ilateral |           |   (mea                                 |
|      | ooph     |           | n)                                     |
|      | orectomy |           |   ----------- -----                    |
|      |          |           | ---- --------- --------- ------------- |
|      | Renal    |           |                                        |
|      | im       |           | \*significant vs. placebo; \[95% CI\]  |
|      | pairment |           |                                        |
|      |          |           | **AE Withdrawals:** 5%/5%/7%/9%        |
|      | Severe   |           | (0.5/1/2.5/placebo)                    |
|      | vitamin  |           |                                        |
|      | D        |           | **Commonly reported AEs:** dyspepsia,  |
|      | de       |           | gastroenteritis, nausea, GI pain, GI   |
|      | ficiency |           | disorder (similar between all groups)  |
|      |          |           |                                        |
|      | Abnormal |           |                                        |
|      | calcium  |           |                                        |
|      | levels   |           |                                        |
|      |          |           |                                        |
|      | CI to    |           |                                        |
|      | calcium  |           |                                        |
|      | therapy  |           |                                        |
|      |          |           |                                        |
|      | Delayed  |           |                                        |
|      | es       |           |                                        |
|      | ophageal |           |                                        |
|      | emptying |           |                                        |
|      |          |           |                                        |
|      | Disorder |           |                                        |
|      | or       |           |                                        |
|      | therapy  |           |                                        |
|      | (within  |           |                                        |
|      | the last |           |                                        |
|      | 6 mos)   |           |                                        |
|      | known to |           |                                        |
|      | affect   |           |                                        |
|      | bone     |           |                                        |
|      | me       |           |                                        |
|      | tabolism |           |                                        |
|      |          |           |                                        |
|      | Previous |           |                                        |
|      | t        |           |                                        |
|      | reatment |           |                                        |
|      | with     |           |                                        |
|      | bisphos  |           |                                        |
|      | phonates |           |                                        |
|      |          |           |                                        |
|      | T        |           |                                        |
|      | reatment |           |                                        |
|      | with     |           |                                        |
|      | investi  |           |                                        |
|      | gational |           |                                        |
|      | drug in  |           |                                        |
|      | past 30  |           |                                        |
|      | days     |           |                                        |
|      |          |           |                                        |
|      | Fluoride |           |                                        |
|      | t        |           |                                        |
|      | reatment |           |                                        |
|      | in past  |           |                                        |
|      | 12 mos   |           |                                        |
|      | or \>2   |           |                                        |
|      | yrs      |           |                                        |
|      | duration |           |                                        |
+------+----------+-----------+----------------------------------------+

AE=adverse event; BMD=bone mineral density; BMI=body mass index;
CI=contraindication; DB=double-blind; ITT=intention to treat;
GI=gastrointestinal; LS=lumbar spine; MC=multicenter;
PC=placebo-controlled; PG=parallel group; PP=per-protocol; PUD=peptic
ulcer disease; RRR=relative risk reduction; TH=total hip