The FOSAMAX Induced Femur Fractures - HB Litigation Conferences

The FOSAMAX Induced
Femur Fractures

FOSAMAX®
(ALENDRONATE SODIUM)
• Manufactured by Merck
• Belongs to class of drugs known
as bisphosphonates, including:
Actonel- Proctor & Gamble
Aredia- Novartis
Boniva- Roche
Didronel- Proctor & Gamble
Reclast - Novartis
Skelid- Sanofi-Aventis
Zometa- Novartis

Fosamax indications include:
• Treatment of osteoporosis in
postmenopausal women
• Treatment to increase bone mass in
men with osteoporosis
• For prevention of osteoporosis, may be
considered in postmenopausal who are
risk of dev osteoporosis and for whom
the desired clinical outcome is to
maintain bone mass and to reduce risk
of future fracture

What is Osteoporosis?:
• A skeletal disorder characterized by
compromised bone strength predisposing to an
increased risk for fracture.
• Bone strength reflects the integration of 2 main
features: 1) bone mineral density (BMD); and 2)
bone quality, (i.e., quantity
and quality of bone)
-- NIH Consensus Statement, 2000.

Normal Moderate Osteoporosis
Severe Osteoporosis

WHO Criteria for Diagnosis of
Osteoporosis: (Measurement of BMD)
-- BMD is typically measured
using a DEXA scanner
-- Results are reported as a T score
T Score Classifications
>-1 Normal
-2.5 to -1 Osteopenia

Pathophysiology of the Injury
The life of the skeleton is a highly active, living
tissue
Our bones are continually eaten
away by osteoclasts…
and rebuilt by osteoblasts…..
and it’s this process of continuous
remodeling that provides our bones with durability.

FOSAMAX:
Mechanism of Injury
• FOSAMAX inhibits osteoclastic mediated bone turnover (remodeling)
which results in increased bone mineralization, which in turn increases
brittleness of bone.
•Microcracks tend to develop within highly mineralized bone.
•Because remodeling is inhibited, microdamage accumulates, and in time,
stress reactions arise which may develop into stress fractures and eventually
complete fractures
•Long term use of Fosamax is associated with reduced bone repair and
accumulation of microdamage, leading to reduced bone toughness and
adynamic fragile bones….and resulting in Atypical Femur Fractures (AFF)
• FOSAMAX well bound in bone and so long lasting; FOSAMAX remains
biologically active for over 10 years after final dose.

FOSAMAX Atypical Femur
Fractures (AFF): A Signature Injury
• Subtrochanteric fracture:
-Area between the lower border of the
lesser trochanter to proximal third of
femur (but can include to distal femur,
less commonly.)
-None to minimal trauma
• Unique radiographic pattern:
a) Cortical thickening of the subtrochanteric
region;
(b) A transverse or oblique fracture
(c) Medial cortical spike
(d) Some with bilateral stress fractures,
(e) Often with associated prodromal pain.

Sample X-Rays of signature injury

Fracture Intervention Trial (FIT)
• FIT consisted of 2 studies in postmenopausal women:
the 3-year study (with vertebral fracture) and the 4-year
study (with low BMD but no vertebral fracture.)
• 3,236 women were treated with Fosamax 5mg for 2
years, then the dose increased to 10mg for a total of 3-
4.5 years.
Results:
• In women without osteoporosis, no clear reduction in
fracture risk
• 3 year: 47% reduction fx risk; 4 year: 44% reduction in
fx risk
Black DM et al. Fracture Risk Reduction vertebral fractures in women who had
osteoporosis (femoral with Alendronate in Women with Osteoporosis: the Fracture
Intervention Trial. J Clin Endoc Metab 2000 85:4118-4124.

Bisphosphonates Odvina et al, 2005
9 patients sustained unusual spontaneous
nonspinal fractures; on alendronate 3-8
yr; bone biopsies showed markedly
decreased matrix synthesis; 6 had delayed
healing for 3 mo to 2 yr.
J, Clin Endorinol Metab 90:1294-1301, 2005

Dr. Susan Ott M.D.
“I believe the current evidence suggests that
bisps should be stopped after 5 yr. Those
patients who remain at high risk of fractures or
who have had fractures despite BP therapy
could be considered for treatment with
intermittent PTH.”
--Editorial, J Clin Endocrin Metab 2005.

S. Cummings, M.D.
“It is reasonable to consider at least a 5-
year holiday for patients who have been
taking alendronate for at least 5 yrs but
continue treatment in those with a high
risk of vertebral fractures.
-- JAMA 296:2601-2610, 2006.

T-1.8; 5 yrs on alendronate;
FIT N = 6,459
FLEX Trial
Placebo N = 3,223 Alendronate N = 3,236
Placebo N = 437
Eligible for FLEX Screening
N = 2,857
Randomized in FLEX
N = 1,099
Alendronate, 5 mg
N = 329
Black D et al., 2006. J Clin Endocr Metab 85:4118-4124.
FIT (3 to 4.5 yrs)
Post-FIT Post FIT (1-2 (1 2 yrs)
FLEX (5 yrs)
Alendronate, 10 mg
N = 333

Flex Fracture Outcome Years 1-3
relative fracture rate
100
80
60
40
20
0
*
VCFx
Fosamax
Placebo
* statistically significant
45% RRR

Flex Fracture Outcome Years 5-10
% sustaining fracture
25
20
15
10
5
0
‡
‡
Hip Fx VCFx Any fx
‡ not statistically significant
‡
Fosamax
Placebo

Management recommendations:
Dr. Joseph Lane
“Lane advised physicians to check markers of bone
metabolism in patients taking bisphosphonates and
consider a drug holiday if bone metabolism appears
to have stopped. He said he and his colleagues now
discontinue bisphosphonate treatment in patients
after 5 years; these patients are given calcium and
vitamin D and are monitored for bone loss during that
holiday. Bisphosphonate treatment is resumed in
patients who experience bone loss, but at the lowest
possible dose. ‘Until we get more data from industry
and the FDA, we are stepping back,’ he said.”
Source: Kuehn, B, 2009. Long-term risks of bisphosphonates probed.” JAMA 301:710-711.

Unusual Mid-shaft Fractures during Long-
term Bisphosphonate Therapy - 2010
13 women (from 2 hospitals) sustained atraumatic
mid-shaft fractures – 11 femur, 1 humerus, and 1
pelvis &right tibia. All had been only standing,
walking, or turning around. 10 were on alendronate (3-
11 yrs) and 3 on risedronate (Actonel) (2-5 yrs). 10
were also on estrogen, tamoxifen, or prednisone. 3 of
the 11 patients with a femur fracture had bilateral
fractures. Of 11 patients with available information, 10
had delayed fracture healing. Among 6 patients who
had bone biopsies, all had severe depression of bone
formation, with minimal or no osteoblasts.
Note the high % who were also on other meds – a likely increased risk factor.
Odvina CV, et al. 2010. Clinical Endocrinology 72:161-168.

Unusual Mid-shaft Fractures during Long-term
Bisphosphonate Therapy - 2010
Conclusion:
“Long-term bisphosphonate therapy may increase the risk of
unusual long bone mid-shaft fratures. This is probably due
to prolonged suppression of bone turnover, which could
lead to accumulation of microdamage and development of
hypermineralized bone.”
“Emerging data suggest that SSBT is a real clinical entity to
be reckoned with. . . Coadministration of estrogens and
SERMS, long-term steroid therapy, near-normal BMD
before BP therapy and low initial bone turnover appear to
be potential risk factors. Given the large number of patients
exposed to bisphosphonates, even a small fraction of
patients at risk of developing SSBT is not trivial and is
clinically relevant.”
Odvina CV, et al. 2010. Clinical Endocrinology 72:161-168.

Structural effects of long-term bisphosphonate
treatment leading to atypical hip fractures
• A DEXA- based study of the histology of bones of 111
osteoporotic postmenopausal women compared 61
treated with alendronate or risedronate for at least 4
years with 50 controls not on BPs. (Pts on HRT,
steroids, etc. were excluded) In the treated group, axial
strength and structural integrity of the improved during
the first 4 years of treatment, but later began to
deteriorate back to baseline.
• This BP effect can be explained by its inhibitory effect
on bone remodeling, which may compromise the bone’s
ability to bear loads and resist fractures. The results
suggest that BP treatment beyond 4 years is
counterproductive.
Ding A et al. 2010. Presentation at the AAOS National Meeting.

Effects of long-term bisphosphonate
use on bone quality.
Bone samples were obtained from 21
postmenopausal women hospitalized with femur
fractures, 12 who’d been on BPs (mean 8.5 yrs)
with 9 who had not. The treated group had
reduced bone tissue heterogeneity of the
mineral: matrix ration and significantly reduced
crystallinity. “Our data suggest that suppression
of bone turnover with long-term BPs results in a
loss of heterogeneity of the tissue properties that
may contribute to the risk of atypical fractures.”
Gladnick B. Donnelly, Lorich, Lane et al, presentation at AAOS, 3/11/2010

Femoral insufficiency fractures associated
with prolonged alendronate therapy -2010
CONCLUSION
“This is the largest study in the literature on
femoral insufficiency fractures and alendronate
therapy. Long-term alendronate use is
associated with insufficiency fracture of the
femoral shaft, which commonly presents with
prodromal thigh pain and may be bilateral.
Consideration should be given to ceasing
alendronate therapy after 3 to 5 years of
continuous use.”
Isaacs JD et al. Presentation at AAOS 3/12/10

Black 2010: Risk of atypical femur fractures
This study combined results of 3 large prior placebo-controlled studies of
bisphosphonates: FIT (3-4.5 years on Fosamax, 5 mg for first 2 years, then 10 mg)
and FLEX (additional up to 5 years on Fosamax) and HORIZON (up to 3 years on
annual zolendronic acid). Among 14,195 women, 284 records showed hip or femur
fractures, of which 12 were classified as subtrochanteric or diaphyseal, a combined
rate of 2.3 per 10,000 patient-years.
The authors calculated that treating 1,000 women with BPs for 3 years would prevent
100 fractures, while the risk of atypical femur fractures would be about 0.3 cases.
“The occurrence of [such] fractures of the femur was very rare, even among women
who had been treated with bisphosphonates for as long as 10 years. There was no
significant increase associated with bisphosphonate use, but the study was
underpowered for definitive conclusions.”
-Black et al., 2010. Bisphosphonates and fracture of the subtrochanteric or
diaphyseal femur. New England J Medicine 361:1761-71.

Management recommendations: Post-op
1. Discontinue bisphosphonate; consider
teriparatide (Forteo) post-op.
2. Careful long-term follow-up for other fractures;
imaging if pain in other leg. Bone scan if stress
fracture is suspected.
3. If stress fracture is found in other leg, do
prophylactic rodding.
DasDe S. et al, 2010. A rational approach to management of alendronate-related
subtrochanteric fractures. J Bone Joint Surg 92:679-86.

Recent Studies:
JAMA-Canadian Study
NEJM-Swedish Study

JAMA, Park-Wyllie 2011:
BP Use and the Risk of ST or Femoral Shaft
Fractures in Older Woman (Canada)
Adjusted OR 2.74
With BP use > 5 years

NEJM: Schilcher, et al: BP Use and
Atypical Fractures of the Femoral Shaft
• 12,777 woman, age 55 sustaining femur fx in 2008
• Reviewed 1234 x-rays reviewed of shaft fx
• 59 patients with AFF indentified, 78% of these on BP (Longest
duration of use 3 years)
Results:
Age adjusted RR 47.3
Risk higher with longer use (OR 1.3). Risk was 10x as compared
to normal risk within 2 years of use and 50X as high thereafter.
Conclusion: “Absolute risk of atypical fractures associated with BP
for patients with a high risk of osteoporotic fractures is small as
compared with beneficial effects of the drug.”
Schilcher, et al 2011, BP Use and Atypical Fractures of the Femoral Shaft

Fosamax Label:
Timeline

March 10, 2010

Fosamax 2010 Task Force Report

ASBMR Symposium
October 2010, Toronto
• Task force of the American Society for Bone and
Mineral Research (27 international experts)
Results and Conclusions
- Defined AFF
- AFF associated with long-term BP use but no causal link
- Data suggests that risk rises with increasing duration of
exposure
- Concern that lack of awareness and under-reporting may
mask true incidence.

Information for FDA warning to doctors regarding
BP-related femur fractures:
• Fx are often bilateral. If one femur has a stress or completed
fracture, assess the contralateral femur.
• BP treatment should be stopped as soon as a stress or
completed fracture is diagnosed.
• Completed fractures are often preceded by stress fractures,
which frequently cause thigh pain. Thigh pain in a patient
on long-term BPs requires assessment with imaging studies.
• BP-related stress fractures are at high risk of completion,
and require early referral to an orthopedist for treatment
(which often is prophylactic rodding).
• BP-related fractures are at high risk of non-union or delayed
union.
• Despite stopping the BP, patients remain at risk for years of
additional fractures and need to be followed up.

FDA Announces Label Change:
October 13, 2010
• FDA announced that it will be updating the public regarding
information previously communicated regarding the risk of AFF
in patients who take BP for osteoporosis (Class warning).
• This information will be added to the Warnings and Precautions
section of the label
• “FDA will require a new Limitations of Use Statement in the
Indications and Usage section of the label
• “FDA will require that a Medication Guide be included with all
BP medications approved for osteoporosis”
-Based upon on-going FDA review and Task Force data of ASBMR

Fosamax Label
Warnings/Precautions:
Pre-January 2011
• No Warnings or Precautions regarding AFF
• No long term studies were performed according to label:
– “The efficacy of FOSAMAX has been established in studies of two
years’ duration. The greatest increase in bone mineral density
occurred in the first year with maintenance or smaller gains during
the second year. Efficacy of FOSAMAX beyond two years has not
been studied.”

Jan. 2011: Update on Femur Fracture Risk with
Bisphosphonates

Fosamax Label
Warnings/Precautions:
Precautions Section
Issued January 2011
“Atypical Subtrochanteric and Diaphyseal Femoral Fractures”
• AFFs have been reported
• Location of AFF
• “Causality has not been established as these fractures also
occur in osteoporotic patients who have not been treated
with BP.”
• Occur with minimal or no trauma, may be bilateral with
prodromal pain
• Number of reports note patients also txed with
glucocorticoids

Fosamax Label
Warnings/Precautions:
Issued January 2011: (Continued)
Precautions Section
“Atypical Subtrochanteric and Diaphyseal Femoral Fractures”
• Patients with hx of BP exposure with thigh/groin should be
suspected for AFF and evaluated to rule out for incomplete
femur fx.
• Patients with AFF should be assessed for s/s of fx on
contralateral limb
• Interruption of BP should be considered, pending a
risk/benefit assessment, on individual basis.

Jan. 2011: Update on Femur Fracture
Risk with Bisphosphonates
• FDA recommends that healthcare professionals:
• be aware of the possibility of atypical femur fractures in patients taking bisphosphonates
• rule out a femoral fracture if a patient presents with new thigh or groin pain, and discontinue
potent anti-resorptive medications, including bisphosphonates, in patients who have evidence of a
femoral fracture.
• consider periodically re-evaluating whether continued bisphosphonate therapy is needed,
especially in patients who have been treated for more than five years. Periodic reevaluation is
recommended because the fracture reduction efficacy of these drugs has not been established, and
the optimal duration of use is uncertain.
• discuss the benefits and risks of these drugs with patients, and instruct them to seek medical
attention if they experience new groin or thigh pain, which may be described as dull or aching. This
pain can occur weeks or months before a complete fracture occurs.
This safety information will appear in the drugs' labeling, as well as in a Medication Guide that will
be distributed to patients with each prescription.

http://www.fda.gov/AdvisoryCommittees/Calendar/ucm262477.htm

FDA Bisphosphonate
Advisory Committee Hearing
Deadlines and Dates:
Request to Speak August 17, 2011
Written Submissions August 25, 2011
Hearing September 9, 2011

AdComm Hearing Location
Marriott Inn and Conference Center
University of Maryland University
College (UMUC)
3501 University Blvd. East
Adelphi, Maryland

FDA BP AdComm Speaker and Written
Submission Contact Information
Kalyani Bhatt
Center for Drug Evaluation and
Research
Food and Drug Administration
10903 New Hampshire Avenue
WO31-2417
Silver Spring, Maryland 20993-0002
Phone: 301-796-9001
Fax: 301-847-8533
E-mail: ACRHD@fda.hhs.gov

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