Zoledronic acid

Hadaya Gharibyar, PharmD
PDIC
USA
Canada
UK
UAE
Approved
Approved
Approved
Approved
1. Electronic Medicines Compendium http://emc.medicines.org.uk/
2. http://www.fda.gov/orphan/designat/index.htm
3. Health Canada: http://205.193.93.51/dpdonline/searchRequest.do
Postmenopausal osteoporosis
Bone metastasis- solid tumor configuration
Hypercalcemia of malignancy
Multiple myeloma
Osteopenia
Paget’s disease
Bisphosphonate, Calcium Regulator
Inhibits bone resorption. This MOA is not fully
understood and several factors are thought to
contribute to this action
ZA is an inhibitor of osteoclast-mediated bone
resorption
The main molecular target of ZA is attributable to
its:
◦ High affinity for the active site of farnesyl pyrophosphate
(FPP) synthase
◦ Its strong binding affinity to bone mineral
1. Micromedex series- 2008
Once-yearly zoledronic acid
postmenopausal osteoporosis
for
treatment
of
Zoledronic acid and clinical fractures and mortality
after hip fracture
Head-to-head study pending:
◦ Safety/efficacy
of
zoledronic
acid
alendronate
on
bone
metabolism
postmenopausal women with osteoporosis
and
in
ClinicalTrials.gov. Safety/efficacy of zoledronic acid and alendronate on bone metabolism in
postmenopausal
women
with
osteoporosis.
Available
online
at:
http://clinicaltrials.gov/ct/show/NCT00404820?order=1. Accessed 11/12/2006.
Once-yearly zoledronic acid for treatment of
postmenopausal osteoporosis: HORIZON- Health
Outcomes and Reduced Incidence with Zoledronic
Acid Once Yearly Pivotal Fracture Trial
By
Black DM, et al
5. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA,
Cosman F, Lakatos P, Leung PC, Man Z, Mautalen C, Mesenbrink P, Hu H, Caminis J, Tong K, Rosario-Jansen T, Krasnow J, Hue TF,
Sellmeyer D, Eriksen EF, Cummings SR; HORIZON Pivotal Fracture Trial. N Engl J Med. 2007 May 3;356(18):1809-22.
International, multi-center, randomized, double-blind, placebo
controlled trial
IV ZA 5 mg (n=3889) vs. Placebo (n=3876) at entry, 12 m, 24 m
Followed quarterly by phone with clinic visit at 6, 12, 24, 36
months
All Pt’s received daily Ca (1 to 1.5 gm) + Vitamin D (800 IU to 12
IU)
Inclusion criteria
– Postmenopausal women (ages 65-89)
– BMD T score less than or equal to -2.5 at femoral neck, with
or without evidence of existing vertebral fracture or
– T Score less than or equal to -1.5 with radiologic evidence of
at least 2 mild vertebral fractures or 1 moderate vertebral
fracture
Exclusion criteria
– Previous PTH use, strontium
– Use of anabolic steroids or GH within previous 6 months
– Use of systemic steroids within 12 months
– Serum Ca greater than 2.75 mmol or less than 2 mmol/L
– CrCl less than 30 ml/min
Reduced
Risk
Zoledronic
acid n=3889
Placebo
n=3876
Relative
Risk
95% CI
P value
3 yr new
vertebral
fracture (in pts
not taking
concomitant
osteoporosis
drugs
70%
3.3%
10.9%
0.30; CI
0.24 to
0.38
Less than 0.001
Incidence of
hip fracture (all
pts)
41%
1.4%
2.5%
0.59; CI
0.42 to
0.83
Less than 0.001
Primary
outcomes
Incidence of secondary endpoints for fracture (including
nonvertebral fractures, all clinical fractures, and clinical
vertebral fractures) were significantly reduced by 25%, 33%,
and 77%, respectively (p less than 0.001 for all comparisons)
Pts in ZA group had significantly less height loss (-4.2mm)
than patients in the placebo group (-7.0 mm, p less than
0.001)
Bone mineral density increased significantly at the total hip,
lumbar spine, and femoral neck by 6.02%, 6.71%, and 5.06%,
respectively, as compared with the placebo group (p less than
0.001 for all comparisons)
At 12 months, lover serum C-telopeptide of type I collagen,
bone-specific alkaline phosphatase, and N-terminal
propeptide of type I collagen were 59%, 30%, and 58% lower,
respectively, in the zoledronic-acid group (p less than 0.001
for all comparisons)
Adverse events, including changes in renal function, were
similar
Serious atrial fibrillation occurred more frequently in the
zoledronic acid group compared to placebo (in 50 vs. 20
patients, P less than 0.001)
4. Gluud LL, Kjaer MS, Christensen E. Terlipressin for hepatorenal syndrome. Cochrane Database of Systematic
Review 2006, Issue 3. Art. No.: CD005162. DOI: 10.1002/14651858.CD005162.pub2
◦ A once-yearly infusion of zoledronic acid
during a 3-year period significantly
reduced the risk of vertebral, hip, and
other fractures.
Zoledronic Acid and Clinical Fractures and
Mortality after Hip Fracture: HORIZON
Recurrent Fracture Trial
By
Lyles KW, Colón-Emeric CS, Magaziner JS, Adachi JD, Pieper CF, Mautalen C, Hyldstrup L, Recknor C,
Nordsletten L, Moore KA, Lavecchia C, Zhang J, Mesenbrink P, Hodgson PK, Abrams K, Orloff JJ,
Horowitz Z
5. Zoledronic acid and clinical fractures and mortality after hip fracture. Lyles KW, Colón-Emeric CS, Magaziner JS, Adachi JD, Pieper CF, Mautalen C,
Hyldstrup L, Recknor C, Nordsletten L, Moore KA, Lavecchia C, Zhang J, Mesenbrink P, Hodgson PK, Abrams K, Orloff JJ, Horowitz Z, Eriksen
EF, Boonen S; HORIZON Recurrent Fracture Trial. N Engl J Med. 2007 Nov 1;357(18):1799-809. Epub 2007 Sep 17
International, multi-center, randomized, double-blind, placebo controlled
trial involving patients with recent hip fracture
IV ZA 5 mg (n=1065) vs. Placebo (n=1062) at entry, 12 m, 24 m
Pt’s monitored for up to 5 years with quarterly phone interviews and
yearly clinic visits
All Pt’s received daily Ca (1 to 1.5 gm) + Vitamin D (800 IU to 1200 IU)
Inclusion criteria
– All Pts who had undergone repair of a hip fracture and unwilling to take an
oral bisphosphonate
– Men and women 50 years or older were eligible for inclusion if within 90
days after surgical repair of a hip fracture sustained with minimal trauma
– Being ambulatory before hip fracture and having both legs
Exclusion criteria
–
–
–
–
Previous hypersensitivity
Potential pregnancy
CrCl less than 30 ml/min
A corrected serum calcium level of more than 11.0 mg/dL or less than 8.0
mg/dL
– Active cancer
– Metabolic bone disease other than osteoporosis
– Life expectancy less than 6 months in the investigator’s judgment
Primary
outcomes
Relative
Risk
Reduction
Zoledronic acid
n=1065
Placebo
n=1062
P value
New clinical
fractures
35%
8.6%
13.9%
Less than 0.001
New clinical
vertebral fractures
1.7%
3.8%
Less than 0.02
New clinical nonnonvertebral fractures
7.6%
10.7%
P=0.03
2.0%
3.5%
Not significant
New hip fractures
30%
Bone mineral density at the total hip increased in
the ZA group by 2.6% at 12 months, 4.7% at 24
months, and 5.5% at 36 months and declined in the
placebo group by 1.0%, 0.7%, and 0.9%,
respectively. (p less than 0.001)
Bone mineral density at the femoral neck increased
in the ZA group by 0.8% at 12 months, 2.2% at 24
months, and 3.6% at 36 months and declined in the
placebo group by 1.7%, 2.1%, and 0.7%,
respectively. (p less than 0.001)
There were a total of 242 of 2111 patients (11.5%) who died
during the study
101 of 1054 were from the ZA group (11.5%) vs. 141 of 1057
(13.3%) were in the placebo group (hazard ratio for the ZA
group, 0.72; 95% CI, 0.56 to 0.93; P=0.01)
More patients in the ZA group reported pyrexia (8.7% vs.
3.1%), myalgia (4.9% vs. 2.7%), bone pain (3.2% vs. 1.0%), or
musculoskeletal pain (3.1% vs. 1.2%)
The incidence of cardiovascular events were similar in the two
groups.
Atrial fibrillation occurred in 12 pts in the ZA group vs. 14 pts
in the placebo group
An annual infusion of zoledronic acid within
90 days after repair of a low-trauma hip
fracture was associated with a reduction in
the rate of new clinical fractures and with
improved survival
National Health Services (UK)
AETNA
Caremark
Anthem
Cigna
Veterans Affairs (VA)
Blue Cross and Blue Shield