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Evidence-Based Management
of Osteoporosis
A Systematic Review of Agents
Currently Available for Osteoporosis
and their Use in Clinical Practice
Benefits of Therapy: Summary
Contemporary pharmacologic treatments
significantly decrease fracture risk:
► “Antiresorptive” therapy produces a modest
increase in bone mineral density (BMD)
► However, decreases in fracture risk—especially
in the spine—occur much faster and to a larger
extent than predicted by the relatively small
change in BMD. This implies an important
improvement in bone “quality”
► Anabolic therapy with teriparatide increases
BMD more than antiresorptive treatment, but it is
not yet obvious that fracture protection is
greater
Objective of Intervention
The most important clinical
objective is the prevention of
fractures—both vertebral and nonvertebral fractures
Changes in surrogate markers--bone
mineral density (BMD) and biochemical
markers of bone turnover--are
“necessary” but are not “sufficient”
Non-Pharmacological Options
►
Nutrition: Wide range of nutrients studied
– Calcium supplementation as needed (1500
mg total intake)
– Vitamin D as needed (400 IU to 800 IU daily)
►
Exercise: Multiple health benefits
►
Fall prevention and/or hip protectors in
the frail elderly
►
Other lifestyle modifications
– Avoiding alcohol and tobacco abuse
Non-Pharmacological Options
►
Taken as a whole, non-pharmacological
options seem to be relatively inexpensive
and modestly effective
►
Exercise, in particular, has other health
benefits, although the same is likely to be
true for diet optimization
►
Optimization of diet, exercise, and fall
prevention should be viewed as an
important adjunct to the pharmacologic
treatment of osteoporotic patients
FDA-Approved Therapeutic Options
Prevention
Treatment
Stops bone loss
Reduces vertebral fractures
Estrogen
Calcitonin (Miacalcin, Fortical)
Alendronate (Fosamax)
Risedronate (Actonel)
Ibandronate (Boniva: oral, injection)
Raloxifene (Evista)
PTH (Forteo)
Normal Coupling of Bone Remodeling
Treatment Agents: Mechanism of Action
Resorption = Formation
► Most treatment agents (bisphosphonates, SERMs,
calcitonin, estrogen) act primarily on the left side
of the equation—to decrease bone resorption
► A decrease in resorption is followed by a decrease
in formation
► Only teriparatide acts on the right side of the
equation—to stimulate formation
Antiresorptive Treatment: Summary
► Antiresorptive
treatment produces a
decrease in the biochemical markers of
bone turnover and a modest increase in
BMD
► Because
a decrease in resorption is
followed by a decrease in formation, BMD
improvement tends to “plateau” after
several years
Antiresorptive Treatment: Summary
►
Antiresorptive treatment decreases fracture risk
much more rapidly and to a larger extent than one
would predict from the relatively small changes in
BMD
Note: Fracture protection can be observed in the
absence of a significant change in BMD
►
Fracture protection persists even when the BMD
reaches a plateau
►
Fracture reduction is most conspicuous in older
patients with prevalent vertebral fractures
Antiresorptive Agents: Clinical Efficacy
Trials of Different Agents Cannot Be Compared Directly
►
For the prevention of osteoporosis, agents must
demonstrate protection against bone loss—typically
in a population of early postmenopausal women
►
For the treatment of osteoporosis, agents must
demonstrate protection against fracture—typically,
against vertebral fracture in a population of older
postmenopausal women with low BMD, with or
without prevalent vertebral fractures
►
Not every treatment agent has been evaluated in a
clinical trial with sufficient statistical power to
examine protection against nonvertebral fracture. in
general—or hip fracture, in particular
Calcium and Vitamin D Reduce
Nonvertebral Fracture Incidence
15
Cumulative incidence (%)
Placebo
Calcium-vitamin D
P = 0.02
10
0
0
6
12
18
Month
Dawson-Hughes B, et al. N Engl J Med 1997;337:670-6
24
30
36
Vitamin D Insufficiency (<30 ng/mL):
Prevalence by Latitude
n=259/532
(48.7%)
42 N
n=342/642
(53.3%)
35 N
n=198/362
(54.7%)
P = NS for Test of Trend
Holick MF, et al. J Clin Endocrinol Metab 2005;90:3215-24
Estrogen Treatment (ET)
►Several approved oral and transdermal
preparations available
►Approved for prevention (not treatment) of
osteoporosis
►Treats symptoms of low estrogen levels
►Skeletal effects
– Decrease in biochemical markers of 50-60%
– 2-year BMD increase of 4-6% at hip and spine
– Decreased incidence of vertebral and hip fractures (34%)
after 5 years in the WHI
– Effects in women with osteoporosis have not been
evaluated in randomized controlled trials
Writing Group for the WHI. JAMA 2002;288:321
Estrogen Treatment (ET)
Current Status of Estrogen for Osteoporosis
►Long-term use not recommended
►Adverse effects may outweigh
benefits
Writing Group for the WHI. JAMA 2002;288:321
Calcitonin
► Calcitonin: 200 units daily by nasal spray
► Approved for treatment (not prevention)
► Skeletal effects:
– Decrease in biochemical markers of 20%
– Small effect (1-2%) on bone density in spine
– Reduced incidence of vertebral fractures (36%) in
women with pre-existing vertebral fractures
– No effect on non-vertebral or hip fractures has been
observed
► Adverse effects: nasal stuffiness
Chesnut CH, et al. Am J Med 2000;109:267-276
Raloxifene
►Raloxifene 60 mg daily
►Approved for both prevention and treatment
►Skeletal effects:
– Decrease in biochemical markers of 30%
– 3-year BMD increases of 2-3% at hip and spine
– Decreased incidence of vertebral fractures (30-50%) in
women with pre-existing vertebral fractures or low bone
density. No effect on non-vertebral or hip fractures has
been observed.
►Adverse effects: hot flashes, venous thrombosis,
leg cramps
►Extra-skeletal effects: Reduction in breast cancer
Ettinger B, et al. JAMA 1999;282:637-645
Bisphosphonates
Risedronate, Alendronate and Ibandronate
Three bisphosphonates are available for prevention
and treatment of osteoporosis—in daily oral,
intermittent oral, and intermittent parenteral
formulations:
►
Risedronate (Actonel®): 5 mg daily or 35 mg weekly
►
Alendronate (Fosamax®): 10 mg daily or 70 mg
weekly for treatment, 5 mg daily or 35 mg weekly for
prevention; available as oral suspension
►
Ibandronate (Boniva® ): 2.5 mg daily or 150 mg
monthly by mouth; 3 mg iv over 15-30 seconds every
3 months
Bisphosphonates
Risedronate, Alendronate and Ibandronate
► Approved
Indications
– Treatment and prevention of postmenopausal
osteoporosis (ibandronate, risedronate,
alendronate)
– Treatment and prevention of glucocorticoid-induced
osteoporosis (risedronate)
– Treatment of glucocorticoid-induced osteoporosis
(alendronate)
– Treatment of men with low bone density
(alendronate)
Bisphosphonates
Risedronate, Alendronate and Ibandronate
► Approval
for these diverse indications was
based on studies performed with daily oral
bisphosphonate administration
► No studies of approved intermittent dosing
(weekly, quarterly, monthly) were designed
with a primary fracture endpoint; all examined
the surrogates BMD and biochemical markers
► Intermittent ibandronate dosing regimen with
extended dose-free intervals demonstrated
50% fracture reduction at 3 years as primary
end point
BMD Changes with Bisphosphonates
►
There are no head-to-head clinical studies
comparing ibandronate to other
bisphosphonates in terms of BMD changes
or fracture reduction
►
In the absence of head-to-head clinical
studies, comparisons of efficacy such as
BMD changes and fracture reduction between
bisphosphonates should not be made
Extended Dosing
► Extended
dosing is based on the hypothesis that
the intermittent administration of a medication
will have a durable clinical benefit
► That
durable benefit would ideally be assessed
by a “hard” clinical endpoint such as fracture
protection
► Absent
that clinical endpoint, the benefit could be
assessed indirectly by pharmacokinetics and the
effects of treatment on surrogate endpoints such
as BMD and biochemical markers of turnover
Extended Dosing
►A
successful extended dosing regimen
would presumably show an effect on
biochemical markers of bone turnover—
but it’s not obvious a priori what the
ideal marker profile might be
►A
successful dosing regimen would
also presumably show an effect on BMD
at diverse sites—but it’s again not
obvious what the ideal BMD response
might be
Extended Dosing
► The
“bridging” approach has been based on the
assumption that extended dosing will reduce
fracture risk if the extended dosing affects the
surrogates—markers and BMD—in a fashion that
is “non-inferior” to standard, daily dosing that
has been proven to reduce fracture risk
Bridging From Daily to Less
Frequent Dosing Regimens
Daily
bisphosphonate
regimen
(with proven
antifracture
efficacy)
Regimens shown to be
equivalent in terms of
lumbar spine BMD at
1 year, using
non-inferiority or
equivalence tests
Less frequent
bisphosphonate
dosing regimen
On this basis, weekly alendronate1 and risedronate2 and
monthly ibandronate are assumed to be able to produce similar
antifracture efficacy to their respective daily regimens
1.
2.
3.
Schnitzer T, et al. Aging Clin Exp Res. 2000;12:1-12.
Brown JP, et al. Calcif Tissue Int. 2002;71:103-111.
Miller P et al, J BoneMin Res, 2005, 20, 8, 1315-1322
BMD Results for Alendronate
Precedent for Applying
the Bridging Concept: Alendronate
● Equivalence study comparing
35 mg twice weekly and 70 mg once
weekly to 10 mg daily alendronate
Alendronate
10 mg daily
● Inclusion criteria
oral
– Females 40-90 years old
– ≥ 2 years since menopause
Primary endpoint =
equivalence of
– Lumbar spine or femoral neck Tscore ≤ -2.5, or prior vertebral or hip
fracture
● Daily supplementation with 500 mg
calcium and 250 IU vitamin D
● 30-minute post-dose fast
lumbar spine BMD
at Year 1
Alendronate
70 mg
weekly oral
In the absence of head-to-head studies, the results obtained from different clinical
trials should not be compared.
Schnitzer T, et al. Aging Clin Exp Res. 2000;12:1-12.
Alendronate:
BMD Results (Daily vs Weekly) Year 1
8.0
Mean % Change
in BMD From Baseline
7.0
10 mg Daily at Year 1
70 mg Once Weekly at Year 1
6.0
5.0
4.0
3.0
2.0
5.4
5.1
3.1
1.0
2.9
2.9
4.4
3.9
2.3
0.0
Lumbar Spine
►
Total Hip
Femoral Neck
Trochanter
Equivalence demonstrated between weekly and daily dosing regimens.
In the absence of head-to-head studies, the results obtained from different clinical
trials should not be compared.
Schnitzer T, et al. Aging Clin Exp Res. 2000;12:1-12.
Alendronate:
BMD Results (Daily vs Weekly) Year 1&2
8.0
7.4
Mean % Change
in BMD From Baseline
7.0
10 mg Daily at Year 11
10 mg Daily at Year 22
70 mg Once Weekly at Year 11
70 mg Once Weekly at Year 22
6.8
6.1
5.9
4.4
3.9
6.0
4.3
5.0
4.1
4.0
3.0
2.0
5.4
3.5
3.3
5.1
3.1
1.0
2.9
2.9
2.3
0.0
Lumbar Spine
Total Hip
Femoral Neck
Trochanter
In the absence of head-to-head studies, the results obtained from different clinical
trials should not be compared.
1. Schnitzer T, et al. Aging Clin Exp Res. 2000;12:1-12.
2. Rizzoli R, et al. J Bone Miner Res. 2002;17:1988-1996.
BMD Results with Risedronate
Precedent for Applying
the Bridging Concept: Risedronate
►
►
Non-inferiority study comparing 35 mg
and 50 mg once-weekly to 5 mg daily
risedronate
Inclusion criteria
– Females ≥ 50 years of age
– Postmenopausal ≥ 5 years
– Lumbar spine or femoral neck
T-score ≤ -2.5; or lumbar spine
T-score ≤ -2.0 and at least one prevalent
vertebral fracture
►
►
Daily supplementation with 1000 mg
calcium and 500 IU vitamin D*
30-minute post-dose fast
Risedronate
5 mg daily
oral
Primary endpoint =
non-inferiority of
lumbar spine BMD
at Year 1
Risedronate
35 mg
weekly oral
* For patients with low serum levels of vitamin D at baseline.
In the absence of head-to-head studies, the results obtained from different clinical
trials should not be compared.
Brown JP, et al. Calcif Tissue Int. 2002;71:103-111.
Risedronate:
BMD Results (Daily vs Weekly) Year 1
5 mg Daily at Year 1
8.0
35 mg Once Weekly at Year 1
Mean % Change
in BMD From Baseline
7.0
6.0
5.0
4.0
3.0
2.0
4.0
3.9
2.5
1.0
2.4
2.1
3.3
1.9
3.0
0.0
Lumbar Spine
► Equivalence
Total Hip
Femoral Neck
Trochanter
demonstrated between weekly and daily dosing regimens.
In the absence of head-to-head studies, the results obtained from different clinical trials
should not be compared.
Brown JP, et al. Calcif Tissue Int. 2002;71:103-111.
Risedronate:
BMD Results (Daily vs Weekly) Year 1&2
8.0
Mean % Change
in BMD From Baseline
7.0
6.0
5 mg Daily at Year 11
5 mg Daily at Year 22
5.2
4.7
5.0
2.0
4.7
3.4
4.0
3.0
35 mg Once Weekly at Year 11
35 mg Once Weekly at Year 22
4.0
3.0
2.5
3.9
2.5
1.0
2.4
2.1
1.9
1.9
3.3
4.2
3.0
0.0
Lumbar Spine
Total Hip
Femoral Neck
Trochanter
In the absence of head-to-head studies, the results obtained from different clinical
trials should not be compared.
1. Brown JP, et al. Calcif Tissue Int. 2002;71:103-111.
2. Harris ST, et al. Curr Med Res Opin. 2004;20:757-764.
BMD Results for Ibandronate
Applying the Bridging Concept:
Ibandronate
► Non-inferiority
Ibandronate
2.5 mg oral
daily
Primary endpoint =
non-inferiority of
lumbar spine BMD
at Year 1
Ibandronate
150 mg
once-monthly
oral
study comparing
100 mg and 150 mg once-monthly
to 2.5 mg daily ibandronate
– If non-inferiority was demonstrated, a
pre-planned statistical superiority test
was conducted
► Inclusion
criteria
– Females 55-80 years old
– ≥5 years since menopause
– Mean lumbar spine (L2–L4) BMD
T-score <–2.5 and ≥–5.0
► Daily
supplementation with 500 mg
calcium and 400 IU vitamin D
► 60-minute
Miller PD, et al. J Bone Miner Res. 2005;20:1315-1322.
post-dose fast
Ibandronate :
BMD Results (Daily vs Monthly) Year 1
8.0
Ibandronate 2.5 mg Daily at Year 1
Ibandronate 150 mg Monthly at Year 1
Mean % Change
in BMD From Baseline
7.0
6.0
5.0
4.0
3.0
2.0
1.0
3.7
(314)
4.8
(314)
0.0
Lumbar Spine
Year 1
P=0.001
vs 2.5 mg daily
►
►
2.0
(315)
3.0
(316)
Total Hip
P<0.0001
1.7
2.2
(315)
(316)
Femoral Neck
P=0.09
3.2
(315)
4.6
(316)
Trochanter
P<0.0001
Non-inferiority was demonstrated between monthly and daily dosing regimens.
The monthly dosing regimen was statistically superior at lumbar spine, total hip, and trochanter
Per-protocol population (n).
Data on file (Reference # 161-094, 161-098, 161-173) Hoffmann-La Roche Inc., Nutley, NJ 07110.
Ibandronate:
BMD Results (Daily vs Monthly) Year 1&2
2.5 mg Daily at Year 1
150 mg Monthly at Year 1
150 mg Monthly at Year 2
2.5 mg Daily at Year 2
Mean % Change
in BMD From Baseline
8.0
6.6
7.0
6.0
5.0
4.0
5.0
6.2
(291)
(289)
4.2
(294)
4.0
3.1
(289)
3.0
2.0
1.0
3.7
(314)
4.8
(314)
0.0
Lumbar Spine
Year 1
P=0.001
Year 2
P<0.0001
vs 2.5 mg daily
2.5
(292)
(292)
1.9
2.0
(315)
3.0
(316)
Total Hip
P<0.0001
P<0.0001
(292)
(289)
1.7
2.2
(315)
(316)
Femoral Neck
P=0.09
P=0.0002
Per-protocol population (n).
Data on file (Reference # 161-094, 161-098, 161-173) Hoffmann-La Roche Inc., Nutley, NJ 07110.
4.6
3.2
(315)
(316)
Trochanter
P<0.0001
P<0.0001
Ibandronate: Summary of Daily vs Monthly
BMD Results
►
►
►
Non-inferiority demonstrated between monthly
and daily dosing regimens
The monthly dosing regimen was statistically
superior to the daily dosing regimen in terms of
BMD elevations across all sites at Year 2, per
pre-planned analysis
The increase in BMD between years 1 and 2 was
statistically significant across all sites
Data on file (Reference # 161-094, 161-098, 161-173) Hoffmann-La Roche Inc., Nutley, NJ 07110.
Observations: BMD Changes
Drug
Study design and
primary endpoint results
(compared to daily
regimen)
Significant BMD
elevations from
Year 1 to 2
Alendronate 70 mg
weekly
Equivalence
demonstrated
Not Reported
Risedronate 35 mg
weekly
Equivalence
demonstrated
Not Reported
Ibandronate 150 mg
once-monthly
Non-inferiority and
statistical superiority
demonstrated
Yes
There are no head-to-head clinical studies comparing ibandronate to other bisphosphonates in terms of
BMD changes or fracture reduction In the absence of head-to-head clinical studies, comparisons of efficacy
such as BMD changes and fracture reduction between bisphosphonates should not be made
Miller PD, et al. J Bone Miner Res. 2005;20:1315-1322. Brown JP, et al. Calcif Tissue Int. 2002;71:103-111.
Harris ST, et al. Curr Med Res Opin. 2004;20:757-764. Rizzoli R, et al. J Bone Miner Res. 2002;17:19881996. Schnitzer T, et al. Aging Clin Exp Res. 2000;12:1-12. Data on file (Reference # 161-094, 161-173)
Hoffmann-La Roche Inc., Nutley, NJ 07110.
Responders Analysis
Responders Analysis
►
Categorization of responders is an attempt at differentiating success at
increasing or maintaining BMD (responders) from those with
decreasing BMD
►
MOBILE and FACT studies looked at responders
– % patients with lumbar spine or hip trochanter BMD changes at
baseline1-3
►
There are no head-to-head clinical studies comparing ibandronate to
other bisphosphonates in terms of BMD changes or fracture reduction
►
In the absence of head-to-head clinical studies, comparisons of efficacy
such as BMD changes and fracture reduction between bisphosphonates
should not be made
MOBILE – Monthly Oral iBandronate In LadiEs; FACT – Fosamax Actonel Comparison Trial.
Fosamax is a registered trademark of Merck & Co., Inc.
Actonel is a registered trademark of Procter & Gamble Pharmaceuticals Inc.
1. Rosen CJ, et al. J Bone Miner Res. 2005;20:141-151.
2. Miller PD, et al. J Bone Miner Res. 2005;20:1315-1322.
3. Data on file (Reference # 161-092) Hoffmann-La Roche Inc., Nutley, NJ 07110.
FACT: Results Year 1
% Patients With Lumbar Spine and Trochanter BMD Values ≥
Baseline
100
Patients (%)
80
87.3%*
84.5%*
75.6%
67.8%
60
40
20
Lumbar Spine
Trochanter
Risedronate Alendronate
35 mg/week 70 mg/week
Risedronate Alendronate
35 mg/week 70 mg/week
0
In the absence of head-to-head studies, the results obtained from different
clinical trials should not be compared.
* P<0.001 vs risedronate. Modified intent-to-treat population.
Rosen CJ, et al. J Bone Miner Res. 2005;20:141-151.
MOBILE: Results Year 1
% Patients With Lumbar Spine and Trochanter BMD Values ≥
92.4%**
Baseline
100
90.8%*
83.8%
80.0%
Patients (%)
80
60
40
20
Lumbar Spine
n=314
Trochanter
n=314
n=315
n=316
150 mg
Monthly
2.5 mg
Daily
150 mg
Monthly
0
2.5 mg
Daily
* P= 0.008vs 2.5 mg; **P<0.001 vs 2.5 mg.
Per-protocol population.
Data from one or both sources.
Miller PD, et al. J Bone Miner Res. 2005;20:1315-1322.
Data on file (Reference # 161-094) Hoffmann-La Roche Inc., Nutley, NJ 07110.
Daily and Monthly Oral Ibandronate
► The
MOBILE study examined BMD and
biochemical marker changes with daily
(2.5 mg) and monthly (150 mg)
ibandronate therapy over 1 and 2 years
► The
changes in BMD with monthly
therapy were superior to those seen
with daily treatment
Miller PD, et al. J Bone Miner Res 2005;20:1315-22
Reginster JY, et al. Ann Rheum Dis 2006;65:654-61
Fracture rate/per 100 patients
Relationship between change in BMD and
risk of vertebral fracture: the BONE study
17
16
15
14
13
12
11
10
9
8
7
6
5
4
3
Placebo
Oral daily and intermittent ibandronate
–4
–3
–2
–1
0
1
2
3
4
5
BMD change (%)
Wasnich R, et al. Osteoporos Int 2003;14 (Suppl. 7):S76(Abstract P272)
6
7
8
9
Bisphosphonates
Risedronate, Alendronate and Ibandronate
►
None of the approved intermittent bisphosphonate
regimens (weekly, monthly or quarterly) has
demonstrated protection against vertebral or
nonvertebral fractures
►
Each intermittent regimen was approved on the basis
of changes in BMD and biochemical markers over 1-2
years that were non-inferior (alendronate, risedronate)
or superior (ibandronate) to those observed with
standard daily therapy with the same agent over that
same study period
Bisphosphonates
Risedronate, Alendronate and Ibandronate
Rationale for Approval of Intermittent
Regimens
– In each case, daily oral bisphosphonate
therapy had already demonstrated fracture
protection in other trials
– It was assumed that, if changes in the
surrogates were comparable to daily
therapy in a head-to-head trial, intermittent
therapy would also be effective for fracture
protection
Bisphosphonates
Risedronate and Alendronate
Effects on Markers and Fracture
Prevention
►
Increases of 5-8% in bone density in the spine, and
3-5% in the hip after 3 years
►
Reduced incidence of vertebral fractures by 40-65%
►
Reduced nonvertebral fractures (30-40%), including
hip fractures (40-60%; alendronate), in women with
osteoporosis
Osteoporosis Therapy: Bisphosphonates
Spinal BMD Change with Daily Alendronate
Mean % Change from Baseline
Control
Alendronate 10 mg
10
8
6
4
2
0
-2
6
12
18
24
30
36
Month
48
Liberman UA, et al. N Engl J Med 1995;333:1437-43
Osteoporosis Therapy: Bisphosphonates
Mean % Change from Baseline
Spinal BMD Change with Daily Risedronate
Control
Risedronate 5 mg
10
8
6
4
2
0
6
12
18
Month
Harris ST, et al. JAMA 1999; 282:1344-52
24
30
36
49
Bisphosphonates
Ibandronate
Effects on Bone Markers and Fractures
► Increases
of 6% in bone density in the spine
and increases of 3-5% in the hip after 3 years
of daily treatment
► Reduced
incidence of vertebral fractures by
50%; reduction in non-vertebral fractures in
post-hoc analysis only in patients with
BMD < -3.0
Osteoporosis Therapy: Bisphosphonates
Spinal BMD Change with Daily Ibandronate
Control
Ibandronate 2.5 mg
Mean % Change from Baseline
10
8
6
4
2
0
6
12
18
Month
Delmas PD, et al. Osteoporos Int 2004;15:792-8
24
30
36
51
Bisphosphonates
Side effects
► Randomized
controlled trials: No increase in UGI
complaints
► “Class
warning” regarding UGI symptoms for
bisphosphonates administered orally
– Clinical reports of UGI symptoms: abdominal pain, esophagitis
or dysphagia, with esophageal ulcers in some patients
– GI effects minimized by proper dosing, and possibly, with
intermittent dosing
1 Boniva
PI March 2005, Boniva Injection PI January 2006
Bisphosphonates
►“Class
precautions” regarding infrequent bone,
joint and/or muscle pain
►“Class
precautions” regarding jaw
osteonecrosis
►“Influenza-like
illness” in 4.9% of patients in the
first year of quarterly IV ibandronate
administration vs 3.3% with monthly oral
ibandronate and 0.8-1.1% with daily oral
ibandronate 1
1 Boniva1,
Fosomax, Actonel PIs
Bisphosphonates
►Contraindications
Esophageal stricture or impaired esophageal
motility (alendronate); inability to stand or sit for
at least 30 minutes (alendronate and risedronate)
or 60 minutes (ibandronate)
Hypocalcemia
Note: UGI symptoms are not an absolute contraindication
Use in pregnancy: Class C
Bisphosphonates
Dosing requirements
Tablets should be taken on an empty stomach
after an overnight fast with 6-8 oz of plain water
while patient is in upright position
Patients should not eat or lie down for at least 30
minutes (alendronate and risedronate) or 60
minutes (ibandronate)
Calcium and vitamin D supplements, if needed,
should be taken at a different time of day than
the bisphosphonate
Alendronate is available as an oral solution (70
mg weekly)
Bisphosphonates
Unsettled Issues: Are There Differences
Among Bisphosphonates
►
Effects on BMD and biochemical markers?
►
Magnitude of fracture protection—vertebral, nonvertebral, hip? No head to head trials.
►
Onset of fracture protection?
►
Short-term and long-term tolerability/safety?
►
Adherence to treatment (compliance, persistence)?
►
Effects after discontinuation of therapy—possible “drug
holiday”?
►
Annualized costs of the medication?
Bisphosphonates: FDA-Approved Indications
►
“For the treatment of osteoporosis, Fosamax
increases bone mass and reduces the incidence of
fractures, including those of the hip and spine
(vertebral compression fractures)” 1
►
“In postmenopausal women with osteoporosis,
Actonel increases BMD and reduces the incidence
of vertebral fractures and a composite endpoint of
nonvertebral osteoporosis-related fractures” 2
►
“In postmenopausal women with osteoporosis,
Boniva increases BMD and reduces the incidence of
vertebral fractures” 3
1
Fosamax PI July 2005
Actonel PI January 2006
3 Boniva PI March 2005
2
Summary: Fracture Protection
►
It is not possible to compare the pivotal trials of
different treatment agents vis-à-vis fracture
endpoints, making it difficult and problematic to
draw firm clinical conclusions from attempts at
such comparisons
►
Although pivotal trials studied similar
populations of postmenopausal women, there
were important differences in demographics,
inclusion criteria, and fracture endpoints
►
“The absence of evidence is not evidence of
absence”
Non-Vertebral Fractures: A Summary
Demonstrating Fracture Reduction in Multiple Trials Appears
To Be Related to Assessing Agent Efficacy in High Risk
Stratified Subgroups with low BMD:
• In FIT study, subgroups with lower baseline hip BMD showed
greatest effect: reductions for overall and hip fracture
greatest in those with BMD T-scores < -2.5
• Alendronate meta-analysis of 4 studies: In overall group nonvertebral fracture reduction was about 25%, whereas it was
59% in women with T-scores < -2.5
• In risedronate HIP study, women 70-79 years of age with a
BMD < -3.0 plus risk factor or < -4.0 without risk factor
showed significant hip fracture reduction (40%, p=.009), but
another group without pre-specified low BMDs did not
show significant reductions in hip fracture.
Non-Vertebral Fractures: A Summary
• In BONE study (ibandronate) post-hoc analysis showed
reduced non-vertebral fractures (30%) only in patients with
baseline femoral neck T-score < -3.0; no hip fracture effect
demonstrated
“Because the the incidence of fracture increases as
BMD decreases, it is possible that trials with very
low BMD patients could observe a higher
incidence of hip fractures and thus increase the
chance to detect a therapeutic effect.”
Nguyen, Eisman, Nguyen. Anti-Hip Fracture Efficacy of Bisphosphonates:
A Bayesian Analysis of Clinical Trials (JBMR, Vol 21, No. 1 2006)
Summary: Vertebral Fracture Reduction
Trials of Different Agents Cannot Be Compared Directly
Fracture Rates over 3-5 Years; % Reduction
Calcium
Calcitonin
Raloxifene
Alendronate
Risedronate
Ibandronate
30
25
% of
Patients
with New
Vertebral
Fracture
20
15
36%
49%
30%
41%
10
47%
52%
5
0
1Chesnut
50%
PROOF1 MORE2
FIT VFA3 VERT NA4 VERT MN5 BONE6
OP with Prevalent Vertebral Fractures *
CH, et al. Am J Med. 2000;109:267-76
3Black DM, et al. Lancet 1996;348:1535-41
5Reginster J, et al. Osteoporos Int. 2000;11:83-91
7Cummings SR, et al. JAMA. 1998;280:2077-82
2Ettinger
MORE2 FIT CFA7
OP without Vert Fx *
B, et al. JAMA. 1999;282:637-45
ST, et al. JAMA. 1999;282:1344-52
6Chesnut CH, et al. J Bone Miner Res. 2004;19:1241-9
* All reductions are statistically significant
4Harris
50%
Summary: Nonvertebral Fracture Reduction
Trials of Different Agents Cannot Be Compared Directly
Fracture Rates over 3-5 Years; % Reduction
Included Fractures Varied From Study to Study
Calcium
Raloxifene
Calcitonin
Alendronate
Risedronate
Ibandronate
30
25
% of
Patients
with New
Nonvertebral
Fracture
NS
p = .063
p = .02
p = .063
NS
NS
20
15
33%
20%
10
39%
5
0
1Chesnut
NS
N/A
PROOF1
MORE2 FIT VFA3 VERT NA4 VERT MN5 BONE6
OP with Prevalent Vertebral Fractures
CH, et al. Am J Med. 2000;109:267-76
3Black DM, et al. Lancet 1996;348:1535-41
5Reginster J, et al. Osteoporos Int. 2000;11:83-91
7Cummings SR, et al. JAMA. 1998;280:2077-82
2Ettinger
MORE2 FIT CFA7
OP without Vert Fx
B, et al. JAMA. 1999;282:637-45 (pooled groups)
ST, et al. JAMA. 1999;282:1344-52
6Chesnut CH, et al. J Bone Miner Res. 2004;19:1241-9
N/A = not available; NS = not statistically significant
4Harris
Summary: Hip Fracture Reduction
Trials of Different Agents Cannot Be Compared Directly
Fracture Rates over 3-5 Years; % Reduction
Not All Studies Had Sufficient Statistical Power
Calcium
Calcitonin
Raloxifene
Alendronate
Risedronate
Ibandronate
6
5
% of
Patients
with Hip
Fracture
NS
NS
p = .047
p = .02
NS
4
3
30%
2
51%
1
0
1Chesnut
NS
N/A
PROOF1 MORE2 FIT VFA3 VERT NA4 VERT MN5 HIP8
CH, et al. Am J Med. 2000;109:267-76
3Black DM, et al. Lancet 1996;348:1535-41
5Reginster J, et al. Osteoporos Int. 2000;11:83-91
7Cummings SR, et al. JAMA. 1998;280:2077-82
N/A = not available; NS = not statistically significant
2Ettinger
N/A
BONE6
B, et al. JAMA. 1999;282:637-45 (pooled groups)
ST, et al. JAMA. 1999;282:1344-52
6Chesnut CH, et al. J Bone Miner Res. 2004;19:1241-9
8McClung MR, et al. N Engl J Med. 2001;344:333-40
4Harris
FIT CFA7
Assessment of Fracture Risk Reduction
►
In general, there is a weak relationship between BMD
changes after therapy and fracture risk reduction
►
Changes in BMD after therapy explain an estimated
4% to 28% of the reduction in fracture risk observed
with antiresorptive agents; in fact, some degree of
fracture protection occurs in the absence of a
measured change in BMD in individual patients
►
A change in bone turnover is at least as good a
surrogate for fracture risk reduction as change in
BMD
►
For these reasons, therapeutic efficacy of
antiresorptive agents should be based on fracture risk
reduction outcomes
Eastell R, et al. J Bone Miner Res. 2003;18:1051-56
Summary: Assessment of
Fracture Risk Reduction
►
In trials of different antiresorptive agents, there is
an imperfect relationship between changes in
BMD (or changes in biochemical markers) and the
observed reductions in fracture risk
– Although the trials with different agents are difficult to
compare, the agents associated with smaller changes in
BMD and smaller changes in biochemical markers—
nasal spray calcitonin and raloxifene—have mustered
evidence for vertebral fracture protection only
►
It is not clear that changes in BMD or biochemical
markers can be used to assess fracture risk
reduction in individual patients in clinical practice
Practical Questions and Reasonable
Answers About Antiresorptive Agents
►Use
in combination?
Limited benefit
Increased cost and side effects
Theoretical concern about over-suppression of turnover
Rarely justified
►What happens with continued therapy?
Continued anti-fracture effect of risedronate on vertebral (50%)
and non-vertebral (37%) fractures through at least 5 years 1
Persistent reduction in vertebral fractures (38-50%) over 4
years with raloxifene 2
No abnormalities on bone biopsies after 10 years of
alendronate therapy 3
1 Sorensen
OH, et al. Bone 2003;32:120
Delmas PD, et al. J Clin Endocrinol Metab 2002;87:3609
3 Recker R, et al. J Bone Miner Res 2004:19(Suppl 1):S45 (abstract)
2
Practical Questions and Reasonable
Answers About Antiresorptive Agents
►What
happens when treatment is stopped?
Resumption of bone loss after stopping estrogen and
raloxifene--and probably calcitonin
After 5 years of alendronate, there is some increase in
bone turnover and a decrease in hip BMD over the next 5
years 1
►How
long should therapy be continued?
– Estrogen no longer recommended as the primary
treatment for osteoporosis
– Raloxifene or calcitonin: no limit
– Bisphosphonates
•
•
1 Bone
Long-term in high-risk patients
The effect of stopping therapy on fracture rate is unclear
HG, et al. N Engl J Med 2004;350:1189
Anabolic Agents to Treat Osteoporosis
►
Anabolic agents increase bone mass to a
greater degree than can be achieved with
antiresorptive therapies
►
Anabolic Agents
– Fluoride, GH, IGF-I, strontium ranelate
– Parathyroid hormone and related peptides
(PTH 1-34, PTH 1-84, PTHrP)
Mode of Administration and Dose Determine
the Effect of PTH on Bone
Mode
Effect
Continuous
high dose
Catabolic
Intermittent
low dose
Anabolic
 Recruitment of new osteoblasts
 Osteoblast life span
 Osteoblast activity
Other cellular and regulatory effects
Dobnig H, Turner RT. Endocrinology 1997;138:4607
Osteoporosis Therapy: rhPTH [1-34]
Teriparatide
rhPTH [1-34] (Forteo®) 20 mcg daily subcutaneously
Indication: treatment of men and postmenopausal women with
osteoporosis who are at high risk for fractures
Effects 1
1 Neer
►
Increased bone density in spine by 9% and hip by 3% vs
placebo over 18 months
►
Reduced incidence of vertebral fractures (65%) and nonvertebral fragility fractures (53%) in women with pre-existing
vertebral fractures
►
Studies too small to evaluate effect on hip fractures
RM, et al. N Engl J Med 2001;344:1434-41
Osteoporosis Therapy: rhPTH [1-34]
Teriparatide
►In
–
–
–
–
►In
–
human subjects:
Mild, transient elevation in serum calcium
Mean increase in urine calcium of 30 mg/24 hours. No
statistically significant increase in hypercalciuria
Leg cramps (2.6% vs. 1.3% in controls)
Dizziness (8.0% vs. 5.4% in controls)
rats:
Increased incidence of osteosarcoma with high-dose,
long-term exposure (“Black Box Warning”)
Neer RM, et al. N Engl J Med 2001;344:1434
Practical Questions and Reasonable
Answers About rhPTH [1-34]
►In
which patients?
– Postmenopausal females and males with established
osteoporosis at “high risk” for fractures
►What
pretreatment workup?
– Serum calcium, alkaline phosphatase, PTH
– 25-OH vitamin D, 24-hour urine calcium
►For
how long?
– ≤ 24 months
– No longer-term data on safety or efficacy
►How
much does treatment cost?
– Approximately $800/year for antiresorptives
– $7000/year for teriparatide
Practical Questions and Reasonable
Answers About rhPTH [1-34]
► Given
after an antiresorptive?
– Gains in BMD may be delayed by prior use of alendronate,
but if so, gains are eventually seen
► Given
simultaneously with an antiresorptive?
– No apparent benefit to simultaneous PTH and alendronate
– Early gains appear robust with raloxifene and estrogen,
but no comparison with PTH alone
► Followed
by an antiresorptive?
– Yes, on the basis of current data
► Is
retreatment an option?
– Perhaps, if clinically indicated (but no studies available)
Treatment Summary: “Monotherapy”
► Contemporary
single agents significantly
decrease fracture risk:
– “Antiresorptive” therapy produces a modest BMD
increase, yet decreases fracture risk—especially in the
spine—much faster and to a larger extent than
predicted by the relatively small change in BMD. This
implies an important improvement in bone “quality”
– Anabolic therapy is also now available. Teriparatide
treatment increases BMD more than antiresorptive
treatment, but it is not yet obvious that fracture
protection is greater.
Summary: Predicting Fracture Risk
►
Along with BMD, bone turnover is an important and
independent determinant of fracture risk
►
Among women treated with antiresorptive therapies,
reduction in bone turnover is associated with reduced
fracture risk
►
Change in bone turnover is a rapid predictor of treatmentrelated anti-fracture response in individuals
•
Reduction in bone turnover and increases in BMD are
important indicators of antifracture efficacy of anticatabolic
drugs
– Both for vertebral and nonvertebral fracture
Results cannot be directly extrapolated to anabolic agents
such as fluoride, PTH or strontium ranelate
•
Treatment Summary: Implications
• Fracture risk protection is conferred by a number
of mechanisms: BMD stabilization and/or bone
quality improvement; effects on bone resorption,
all of which should be considered when selecting
therapy
• Fracture protection parameters (i.e.) are important
determinants for reducing fracture risk
• Adherence to drug regimens and ensuring
persistence are important determinants of patient
outcomes
• Patient preferences should be considered