1
Number of hospital bed days
(thousands)
600
548,615
500
400
353,654
352,062
300
200,669
200
131,331
100
0
Osteoporosis
COPD
Lippuner K, et al. Osteoporos Int 1997;7:414–425
Stroke
Breast
carcinoma
MI
Rate per 10,000 per Year
400
300
Men
Hip
Radiographic vertebral
Wrist
400
300
200
200
100
100
0
0
Age (Years)
Data from Europe 1988–1998
Sambrook P, Cooper C. Lancet 2006;367:2010–2018
Women
Age (Years)
Genetic/Non-modifiable






Age
Female sex
Asian or white ethnicity
Previous fragility fracture
Family history of
hip fracture or osteoporosis
Small frame
Potentially Modifiable







Menopause-related estrogen
deficiency
Low body weight
Calcium/vitamin D deficiency
Inadequate physical activity
Excessive alcohol intake
Cigarette smoking
Long-term steroid therapy
(secondary osteoporosis)
National Osteoporosis Foundation (NOF). Available at: http://www.nof.org/osteoporosis/diseasefacts.htm.
Accessed August 31, 2007.
4
 Patient
history, for detection of etiology and
risk factors of osteoporosis.
 Initial physical examination, signs of dorsal
kyphosis could be the consequence of vertebral
compression fractures.
 X-rays or other medical imaging techniques to
detect skeletal pathology and fractures.
 Measurement of BMD to assess low bone mass
 Laboratory tests measuring biochemical
markers of bone turnover.
[NIAMS Osteoporosis Diagnosis, p1].
 All
women aged 65 years or older, regardless of
other risk factors for osteoporosis.
 Postmenopausal women younger than 65 years
who have at least 1 risk factor for osteoporosis
other than menopause, eg:




Family history of osteoporosis.
Personal history of low trauma fracture at age >45.
Current smoking.
Low body weight (< 127 lb).
 All
postmenopausal women who have
experienced a fragility fracture.
According to NOF guidelines, Delaney 2006, pS13
Diagnosis
Normal
BMD T-Score
No lower than −1
Low bone mass [osteopenia] Between −1 and −2.5
−2.5 or less
Osteoporosis
Severe osteoporosis

−2.5 or less with fragility
fractures
T-score = units of standard deviation (SD) that a patient’s BMD is above or
below mean peak bone mass for a young adult woman, measured at the
spine or hip.


Reduction by 1 SD equals a 10%–12% decrease in BMD.
1 SD change increases fracture risk by 1.5- to 2.5-fold.
Adapted from WHO Technical Report Series 921. Geneva: World Health Organization; 2003.
7
 Silent
disease; some fractures may initially go
unnoticed.
 Insufficient
 Poor
rates of diagnosis and treatment.
adherence to prescribed doses:
 Low persistence over time
 Lack of compliance with dosing instructions
Southern Medical Journal • Volume 99, Number 6, June 2006
The Journal of Family Practice, Vol 59, No 6 | JUNE 2010
100
90
% of Patients
80
70
Daily
Weekly
60
50
40
30
20
10
0
P = NS
1
2
3
4
5
6
7
8
9
10 11 12
Months of Continuous Persistence
2
1. Véronique Rabenda , Poor adherence to oral bisphosphonate treatment and its consequences:
a review of the evidence, Expert Opin. Pharmacother. (2009) 10(14):2303-2315
2. Downey TW, et al. South Med J 2006;99:570-575.
9

Poor persistence is particularly associated with complex
administration and frequent dosing1,2

To improve persistence, eliminate the causes of poor persistence.
Complexity of
administration3–5
Frequency of dosing3–
5
Gastrointestinal
intolerability3–5
Poor
persistence
Burden of
polypharmacy
(multiple
medications)3
1. Emkey RD, Ettinger M. Am J Med. 2006;119:S18–S24. 2. Cramer JA, Silverman S. Am J Med. 2006.
3.10Downey TW, et al. South Med J. 2006;99:570–575. 4. Gold DT, et al. Ann Pharmacother. 2006.
5. Sambrook P. Aust Fam Physician. 2006;35:135–137.
 Poor
adherence to daily, weekly, and monthly
regimens of oral bisphosphonates may result
in compromised effectiveness. 1
A
once-yearly IV bisphosphonate therapy
can deliver real-world effectiveness by
assuring adherence for the entire annual
dosing interval 2
1-The Journal of Family Practice, Vol 59, No 6 | JUNE 2010
2- Black DM, et al. N Engl J Med. 2007;356:1809-1822
11
Supplement to Journal of Managed Care Pharmacy JMCP May 2012 Vol. 18, No. 4-b
12


Maximizes attachment

Minimizes detachment
4
KL (L/mol x 106)
High binding affinity for bone
in vitro
Potent FPP synthase inhibition
in vitro

3
2
1
0
CLO ETD RIS IBA ALN ZOL
FPP synthase2
0.5
Maximizes antiresorptive potential
0.4

Minimizes total amount of drug required

Allows single administration of total
annual dose
IC50 (mM)

Binding to Hydroxyapatite1
0.3
0.2
0.1
0.0
ALN
1. Nancollas GH, et al. Bone. 2006;38:617-627.
2. Dunford JE, et al. J Pharmacol Exp Ther. 2001;296:235-242.
14
IBA
RIS
ZOL
PUBLISHED
Zoledronic Acid For
Paget’s Disease
2005–6
PUBLISHED
1.HORIZON Pivotal
Fracture Trial (PFT)
2.HORIZON Recurrent
Fracture Trial (RFT)
2007
PUBLISHED
PUBLISHED
HORIZON Pivotal
HORIZON
Fracture Trial (PFT):1.Glucocorticoid-induced
Bone remodeling Osteoporosis (GIO) Trial
2.HORIZON PFT Trial
(Subgroup Analysis)
2008
2009–10
15
PUBLISHED
HORIZON
PFT extension
study
2012
Zoledronic Acid Extension Study
16
Journal of Bone and Mineral Research, 2012
A
3-year extension of the 3-year HORIZON-PFT
study was performed to address whether
increasing the duration of therapy beyond 3 years
will:
 Maintain BMD
 Provide additional fracture protection
 Reinforce the safety profile established for 3
years of ZOL therapy
PFT = pivotal fracture trial, Dennis Black, University of California, San Francisco, USA, Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a,
Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254
Core study
N = 7,736
Placebo
N = 3,876
1,221 assigned to ZOL
to maintain blinding
(follow up <3 years)
P3Z3
ZOL N = 3,889
HORIZON-PFT
core study
(3 years)
Randomized in extension
N = 1,233
Extension
(3 years)
Placebo
N = 616
Z3P3
Dennis Black, University of California, San Francisco, USA,
Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to t
he HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254
ZOL
N = 617
Z6
19
International, multicenter, double-blind, placebo
controlled extension trial,
 1233 postmenopausal women who received ZOL for 3
years in the core study were randomized to 3
additional years of ZOL (Z6, n.616) or placebo (Z3P3,
n.617).
 All patients received daily oral calcium (1000 to 1500
mg) and vitamin D (400 to 1200 IU).

*All patients received calcium 1000–1500 mg/d and vitamin D 400–1200 IU/d and follow-up telephone calls every 3 months.
FN: femoral neck, BTMs ;bone turn over markers, PBO = placebo, ZOL = zoledronic acid, Dennis Black, University of California, San Francisco, USA, The
Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and
Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254
Primary endpoint:
 Percentage change in FN BMD at Year 6 vs. Year 3.
 Secondary endpoints:
 BMD at other sites, BTMs, fracture incidence &
safety.

*All patients received calcium 1000–1500 mg/d and vitamin D 400–1200 IU/d and follow-up telephone calls every 3 months.
FN: femoral neck, BTMs ;bone turn over markers, PBO = placebo, ZOL = zoledronic acid, Dennis Black, University of California, San Francisco, USA, The
Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and
Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254

Key inclusion criteria1
Postmenopausal women aged ≤ 93 years who received all 3
infusions of study drug in the Core study.
 Randomized ≤ 13 weeks after completing the Core study.


Key exclusion criteria2





Pregnancy.
Prior use of IV bisphosphonate, strontium, sodium fluoride,
PTH.
Use of oral bisphosphonate, systemic corticosteroid, anabolic
steroid or growth hormone without sufficient washout.
Serum calcium < 2 or > 2.75 mmol/L at Core study last visit.
Renal insufficiency with CrCl < 30 mL/min or urine dipstick
> 2+ protein.
CrCl = creatinine clearance; IV = intravenous; PTH = parathyroid hormone; SCr = serum creatinine.
1. Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT),
Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254 2. Black DM, et al. N Engl J Med. 2007;356:1809–1822.
Z6
(n = 616)
Z3P3
(n = 617)
75.5
75.5
353 (57.3)
325 (52.7)
0
256 (41.6)
227 (36.8)
1
177 (28.7)
168 (27.2)
≥2
186 (29.7)
222 (36.0)
Age, years
Mean
Femoral neck T-score, n (%)*
≤ –2.5
Prevalent vertebral fractures, n (%)


On average, patients were 75.5 years old, with >50%
having femoral neck BMD T-scores lower than 2.5 and
approximately 60% with at least one vertebral fracture.
Baseline characteristics between the Z3P3 and Z6 groups
were similar.
*Missing values: Z6, n = 2;Z3P3, n = 2.
Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT),
Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254
24
Change from Baseline (%)
Z6
5
Z3P3
+4.5%
1.36%
(0.58, 2.15)
P = 0.0007
4
3
+3.1%
2
Start of extension
1
Core Study
Extension Study
0
0
1
2
3
4
5
6
Time (Years from Core Study Baseline)
ITT = intention to treat.
Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT),
Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254
Change from Baseline (%)
Z6
8
Z3P3
7
6
5
1.47%
P < 0.0001
4
3
2
1
0
Core Study
0
1
2
Extension Study
3
4
Time (Years)
5
6
* ITT = intention to treat.
Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT),
27
Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254
Change from Baseline (%)
Z6
Z3P3
14
12
10
2.06%
8
6
4
Start of extension
2
0
Core Study
–2
0
Extension Study
1
2
3
4
5
Time (Years from Core Study Baseline)
6
*ITT = intention to treat.
Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT),
28
Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254, P = 0.19
Patients with New Vertebral
Fracture (%)
15
PBO
ZOL Core Study (Yr 0–3)
Z3P3
Z6
70%†
10
For fractures,
we saw 49% lower risk for morphometric vertebral
fractures but no significant difference in clinically49%*
evident
vertebral fractures or nonvertebral fractures.
5
0
Core Study1
** ITT = intention to treat.
Extension Study2
1233 randomized to Extension
Core study:†P < 0.001 relative risk reduction vs. placebo (PBO).
*P = 0.0348, relative risk reduction vs Z3P3; n = the number of patients in the analysis population with X-rays at Year 3 and Year 6
ITT = intention to treat , Z3P3 = ZOL for 3 years and placebo for 3 years, Z6 = ZOL for 6 years.
1. Black DM, et al. N Engl J Med. 2007;356:1809–1822. 2. Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to
30
the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254
Taken together, these efficacy results show that
continuing ZOL for 6 years maintains early gains in BMD
and, by implication, bone strength, but discontinuation
after 3 years also maintains substantial residual benefit.
Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT),
Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254
Mean PINP (ng/mL)
60
Z6
Z3P3
Time of infusion
Start of extension
40
28.8
*
*
20
0
Absolute
difference
at Year 6
3.0 ng/mL
(P =
0.0001)
25.8
Core Study
0
1
2
Extension Study
3
Time (Years)
4
5
6
Mean values remained within the premenopausal reference range throughout
PINP: Procollagen type I N-terminal propeptide, Horizontal dashed lines in green represent premenopausal reference range
(adapted from Black DM, et al. N Engl J Med. 2007;356:1809–1822)
Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT),
32
Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254
Z6
Mean level (ng/mL)
20
15
Z3P3
Time of infusion
Z3P3
9.1%
10
Z6
9.0%
5
0
0
1
2
3
4
Time (Years)
5
Absolute
difference
0.14
ng/mL
P =0.74
(Y0-Y6)
6
BSAP: Bone specific alkaline phosphatase , Horizontal dashed lines in green represent premenopausal reference range (adapted
from Black DM, et al. N Engl J Med. 2007;356:1809–1822).
Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT),
33
Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254
Mean β-CTX (ng/mL)
0.6
0.4
Z6
Start of extension
Z3P3
Time of infusion
0.4
0.3
0.18
0.2
Absolute
difference
Year 0–6
0.03
ng/mL
(P = 0.45)
0.16
0.1
Core Study
0
0
1
2
Extension Study
3
4
5
6
Time (Years)
Mean values remained within the premenopausal reference range throughout.
Horizontal dashed lines in green represent premenopausal reference range (adapted from Black DM, et al. N Engl J Med.
2007;356:1809–1822)
Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT),
34
Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254
0.6
0.4
0.3
0.2
0.1
0
Mean β-CTX (ng/mL)
0.8
Z3P3
Z6
Start of extension trial
*
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
5.5
6
Time (years)
Mean values remained within the premenopausal reference range throughout.
ß-CTX :Beta C-terminal type 1 collagen telopeptide, *P < 0.05. No significant difference at any other time point in the extension
study. Horizontal dashed lines represent premenopausal reference range (Adapted from Black DM, et al. N Engl J Med.
2007;356:1809-1822).
Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT),
35
Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254
36
Z6, n = 613
n (%)
Z3P3, n = 616
n (%)
P value
Total subjects with any AEs
552 (90.1)
552 (89.6)
0.85
Total subjects with any SAEs
191 (31.2)
168 (27.3)
0.15
Total deaths
26 (4.2)
18 (2.9)
0.22
Total discontinuations due
to AEs
14 (2.3)
11 (1.8)
0.55
Category
No increase in risk of AEs or SAEs with long-term (6-Year) ZOL
treatment compared with 3 years of treatment
AE = adverse event; PMO = postmenopausal osteoporosis; SAE = serious adverse event.
Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT),
37
Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254

In general, safety was similar in those continuing ZOL
compared with those who discontinued.

In the extension trail , rates of post dose symptoms
were much lower than active group rates in the core
study and not significantly different between
randomized groups.
Black, University of California, San Francisco, USA, Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized
38
Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February
2012, pp 243–254
38
There were significantly more short-term rises in
serum creatinine 9 to 11 days after infusion in the Z6
versus the Z3P3 group, but these short-term increases
quickly resolved;
 There was no difference between treatment groups
in mean change in creatinine clearance and there
were no long-term differences in any aspect of renal
function.

Black, University of California, San Francisco, USA, Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized
39
Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February
2012, pp 243–254
39
Z6, n = 613
n (%)
Z3P3, n = 616
n (%)
P value
Arrhythmia SAEs
20 (3.3)
11 (1.8)
0.11
Atrial fibrillation SAEs
12 (2.0)
7 (1.1)
0.26
Stroke-related AEs
26 (4.2)
19 (3.1)
0.29
Stroke SAEs
19 (3.1)
9 (1.5)
0.06
Stroke SAEs excluding TIA
13 (2.1)
7 (1.1)
0.18
Death from stroke
4 (0.7)
0 (0.0)
0.06
Myocardial infarction SAEs
5 (0.8)
4 (0.6)
0.75
48 (7.8)
93 (15.1)
0.0001
Category
Hypertension
The difference in cardiovascular events in the Z6 (2.0%) versus Z3P3 (1.1%),
was not statistically significant (P : 0.26).
TIA = transient ischaemic attack.
Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT),
40
Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254
Pivotal Fracture Trial,1, 2
Events, n
Extension Study,*3
New Events, n
Z3
PBO
Z6
Z3P3
(N = 3862) (N = 3852) (N = 613) (N = 616)
Osteonecrosis of the jaw
(ONJ)
Subtrochanteric or diaphyseal
femur fracture†



1
1
1
0
3
2
0
0
No cases of atypical femur fracture or hip or knee
avascular necrosis.
One case of ONJ reported from a patient with risk factors
in Z6 which was resolved with appropriate treatment.
In non-randomized group (P3Z3):
•
1 ONJ case with several ONJ risk factors.
•
1 Subtrochanteric fracture with no atypical features.
*Events were new events that occurred during the extension trial. †Results for the Pivotal Fracture Trial are from a secondary analysis that reviewed fracture records
and radiographs (when available) from all hip and femur fractures to identify those below the lesser trochanter and above the distal metaphyseal flare and to assess
atypical features.
1. Grbic JT, et al. JADA. 2008;139:32–40; 2. Black DM, et al. N Engl J Med. 2010; 362:1761–1771. 3. Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in
Osteoporosis: a, Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254
42

Long-term efficacy results showed that 6 years
of ZOL treatment led to:




Significantly greater increases from baseline in femoral
neck and total hip BMD than discontinuation at 3 years.
Significant risk reduction in vertebral morphometric
fracture risk vs. discontinuation at 3 years.
Maintenance of BTMs within reference range.
Losses in BMD and BTMs in discontinuation group
were modest

Residual benefits after discontinuation suggests that
some patients may discontinue infusions for up to 3
years.
Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the
HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February
43 2012, pp 243–254
 Safety
results were similar in those
continuing ZOL vs. those who discontinued:


Rates of post-dose symptoms were similar and much
lower than that in ZOL group in the Core study.
There is no significant increase in the risk of atrial
fibrillation with ZOL treatment.
 ZOL
treatment for 6 years showed no overall
impact on renal function:

Significantly more transient rises in SCr 9–11 days
after infusion in patients who continued ZOL that
quickly resolved.
Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the
HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254
45
 6-year
data support a positive benefit/risk for
long-term ZOL therapy.
 A post hoc analysis provides insights on which
patients:


May benefit most from continued treatment
beyond 3 years.
May be considered for treatment discontinuation for
up to 3 years.
 Decision
to continue or interrupt ZOL therapy
beyond 3 years should be made on an individual
patient basis.
FDA Advisory Committee. September 9, 2011: Joint Meeting of the Reproductive Health Drugs Advisory Committee and the Drug
Safety and Risk Management Advisory Committee Meeting Announcement. Available at: http://www.fda.gov/downloads/
AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ReproductiveHealthDrugsAdvisoryCommittee/UCM271911.pdf
46
46
 The
existing data do not support a specific
limitation on the duration of use of Aclasta for all
osteoporosis patients.
 However,
based on the reduction in morphometric
fractures, those who are at high fracture risk,
( existing vertebral fractures or with hip
osteoporosis after an initial course of therapy),
may benefit from continued annual infusions.
Effect of 3 Versus 6 Years of Zoledronic Acid Treatment in Osteoporosis: a, Randomized Extension to the
HORIZON-Pivotal Fracture Trial (PFT), Journal of Bone and Mineral Research, Vol. 27, No. 2, February 2012, pp 243–254
FDA Advisory Committee. September 9, 2011: Joint Meeting of the Reproductive Health Drugs Advisory Committee and the
Drug Safety and Risk Management Advisory Committee Meeting Announcement. Available at:
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ReproductiveHealthDrugsAdvisory
47
Committee/UCM271911.pdf
 To
avoid noncompliance problems and the
associated increase in fracture risk, consider IV
bisphosphonates for first-line therapy in women
with postmenopausal osteoporosis.
 The
intermittent dosing regimens of IV
bisphosphonates ensure 100% persistence
throughout the dosing interval.
Adapted from The Journal of Family Practice, Vol 59, No 6 | JUNE 2010 , Postmenopausal osteoporosis: Another
approach to management
48
NEW
49
 Fragility
fractures are associated with increased
morbidity and mortality, so an effective fracture
prevention strategy would have a major impact
on morbidity and a smaller but important impact
on mortality in older adults.1–3
 In
the United States, approximately 10 million
women have osteoporosis and another 34 million
have low bone mass (osteopenia).4
1. NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. Osteoporosis prevention, diagnosis, and therapy. JAMA
2001;285:785–95.
2. Miller RG. Osteoporosis in postmenopausal women. Therapy options across a wide range of risk for fracture. Geriatrics 2006;61:24–30.
3. Brown JP, Josse RG, 2002 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada [published errata appear in
CMAJ 2003;168:400, CMAJ 2003;168:676, and CMAJ 2003;168:544]. CMAJ. 2002;167 (10 Suppl): S1–34.
4. National Osteoporosis Foundation 2008. Available at: http://www.nof.org/osteoporosis/diseasefacts.htm.Retrieved December06, 2009.
References 1-4 are stated in McClung M, Miller P, Recknor C, Mesenbrink P, Bucci-Rechtweg C, Benhamou CL. Zoledronic acid for the prevention of bone loss in
postmenopausal women with low bone mass: a randomized controlled trial. Obstet Gynecol 2009; 114 (5): 999-1007.
50
 Although
women with low bone mass have a
lower fracture risk compared with women of
the same age with osteoporosis, they are at
risk for developing osteoporosis unless bone
loss is prevented.
 Zoledronic
acid has been evaluated for the
prevention of PMO in a 2 year study.
 The study compared a single ZOL acid
infusion or two annual infusions with PBO
(McClung 2009).
51
 24
‐ month, multicenter, randomised,
double‐blind, placebo‐controlled, parallel
group clinical trial in the prevention of bone
loss in postmenopausal women with
osteopenia.
McClung M, Miller P, Recknor C, Mesenbrink P, Bucci-Rechtweg C, Benhamou CL. Zoledronic acid for the prevention of bone loss in postmenopausal
women with low bone mass: a randomized controlled trial. Obstet Gynecol 2009; 114 (5): 999-1007.
52
 To
demonstrate that zoledronic acid given at
randomization and at Month 12 or given at
randomization only was superior to placebo
in % change in lumbar spine BMD at Month 24
in women stratified by time since
menopause(<5years or≥5years).
McClung M, Miller P, Recknor C, Mesenbrink P, Bucci-Rechtweg C, Benhamou CL. Zoledronic acid for the prevention of bone loss in postmenopausal
women with low bone mass: a randomized controlled trial. Obstet Gynecol 2009; 114 (5): 999-1007.
53
 581
female patients aged over 45 years with
osteopenia.
 Stratum I patients : less than 5 years since
menopause.
 Stratum II patients : 5 or more years since
menopause.
McClung M, Miller P, Recknor C, Mesenbrink P, Bucci-Rechtweg C, Benhamou CL. Zoledronic acid for the prevention of bone loss in postmenopausal
women with low bone mass: a randomized controlled trial. Obstet Gynecol 2009; 114 (5): 999-1007.
54
 Zol
5mg infusion at randomization and Month
12 or,
 Zol 5mg infusion at randomization and
placebo infusion at Month 12 or,
 Placebo infusion at randomization and Month
12.
 All patients received calcium 500–1200 mg/d;
vitamin D400–800 IU/d.
McClung M, Miller P, Recknor C, Mesenbrink P, Bucci-Rechtweg C, Benhamou CL. Zoledronic acid for the prevention of bone loss in postmenopausal
women with low bone mass: a randomized controlled trial. Obstet Gynecol 2009; 114 (5): 999-1007.
55
 Significantly,
both Zoledronic acid regimens
were superior to placebo in increasing
lumbar spine, total hip, femoral neck,
trochanter and distal radius BMD at Month
24 and Month 12 in both subpopulations
(Stratum I and II) of postmenopausal women.
McClung M, Miller P, Recknor C, Mesenbrink P, Bucci-Rechtweg C, Benhamou CL. Zoledronic acid for the prevention of bone loss in postmenopausal
women with low bone mass: a randomized controlled trial. Obstet Gynecol 2009; 114 (5): 999-1007.
56
Lumbar spine
Lumbar spine
after 12
Hip after 12
after 24
Hip after 24
months
months
months
months
Percent change in BMD* from baseline in
women received Zol acid once per 2 years
5
4
Aclasta
p ˂ 0.001
Placebo
3
4.42%
2
1
2.33%
2.33%
2.28%
0
-1
-2
-0.38
-0.38
-1.32
-1.45
*The recommended regimen in prevention of postmenopausal osteoporosis is a single IV infusion of 5mg Aclasta
administered once yearly. An annual assessment of patient’s risk of fracture and clinical response to treatment should guide
the decision of when retreatment should occur, Aclasta BPI
McClung M, Miller P, Recknor C, Mesenbrink P, Bucci-Rechtweg C, Benhamou CL. Zoledronic acid for the prevention of bone loss in postmenopausal
women with low bone mass: a randomized controlled trial. Obstet Gynecol 2009; 114 (5): 999-1007.
 Both
once‐yearly ACLASTA and ACLASTA given
at the start of the study significantly
decreased levels of serumβ‐CTx, serum
P1NP and serum BSAP compared with
placebo at all time points over 24 months in
both subpopulations of postmenopausal
women.
McClung M, Miller P, Recknor C, Mesenbrink P, Bucci-Rechtweg C, Benhamou CL. Zoledronic acid for the prevention of bone loss in postmenopausal
women with low bone mass: a randomized controlled trial. Obstet Gynecol 2009; 114 (5): 999-1007.
58
p ˂ 0.001
**Bone Turnover Markers.
* The recommended regimen in prevention of postmenopausal osteoporosis is a single IV infusion of 5mg Aclasta
administered once yearly. An annual assessment of patient’s risk of fracture and clinical response to treatment should guide
the decision of when retreatment should occur. Aclasta BPI
McClung M, Miller P, Recknor C, Mesenbrink P, Bucci-Rechtweg C, Benhamou CL. Zoledronic acid for the prevention of bone loss in postmenopausal
women with low bone mass: a randomized controlled trial. Obstet Gynecol 2009; 114 (5): 999-1007.
Both once-yearly dosing and a single dose
of intravenous zoledronic acid 5 mg
prevented
bone loss for 2 years and were welltolerated in postmenopausal women with
low bone mass.
McClung M, Miller P, Recknor C, Mesenbrink P, Bucci-Rechtweg C, Benhamou CL. Zoledronic acid for the prevention of bone loss in postmenopausal
women with low bone mass: a randomized controlled trial. Obstet Gynecol 2009; 114 (5): 999-1007.
60
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