Disentangling the cause of atypical femur fractures associated with the use of bisphosphonates

Osteoporosis and bisphosphonates
Osteoporosis is a common metabolic bone disease characterized by compromised
bone strength predisposing individuals to an increased risk of fractures, which
are associated with significant morbidity and mortality. It is estimated that
1:3 women and 1:7 men older than 60 years suffer from osteoporosis world-wide.
Approximately 50% of women and 20% of men older than 50 years will sustain an
osteoporosis-related fracture during their lifetime, and 20-25% of patients
will die within 12 months after a hip fracture. Bisphosphonates are a key
element in the treatment of osteoporosis. Randomized trials have shown that
treatment with bisphosphonates substantially reduces the risk of all types of
osteoporotic fractures, including vertebral fractures, non-vertebral fractures
and hip fractures. Recent studies even show that bisphosphonates decrease
mortality, independent of fracture reduction. Bisphosphonates are cheap now
that generic forms are available and are increasingly prescribed all around the
world. For instance Alendronate, a preferred bisphosphonate, was provided
320.000 times in the first six months of 2007 in the Netherlands. In the first
half-year of 2000 that was 97.000 times.

Atypical femur fractures
Following the use of bisphosphonates in millions of patients in clinical
practice, some unexpected possible adverse effects have been reported,
including osteonecrosis of the jaw and atypical femur fractures (AFFs). After
the first publication by Odvina in 2005, numerous case reports of AFFs appeared
and multiple observational studies added evidence that particularly long-term
use of bisphosphonates is associated with increased risk of unusal fractures of
the proximal femur. Thus, AFF may be a severe side-effect of bisphosphonate
use. However, a causal relationship between bisphosphonate use and AFF has not
been established and the pathogenesis of AFFs remains unknown. One hypothesis
is that lowering the rate of bone resorption by bisphosphonates leads to
accumulation of microdamage, because fatigue bone is replaced more slowly. This
phenomenon is called *frozen bone* and results in an increased fragility of the
femoral cortex.
AFF has severe consequences for the patients involved. In most cases the femur
breaks spontaneously or after minimal trauma. Unfortunately AFF often occur
bilaterally and are associated with delayed healing or nonhealing.
The estimated incidence rate is one per 1000 long-term bisphosphonate users per
year. However, the precise incidence is unknown because of a lack of diagnostic
codes and adequately powered prospective studies, while observational studies
are hampered by multiple sources of bias. Possibly AFFs are not always
recognized as such, and therefore underdiagnosed.
Because of the attention given to this rare complication on the internet, by
the treating physicians and by package inserts, patients needing
bisphosphonates lose confidence in this treatment and become non-compliant.
Fear of side effects is a well-known reason for non-compliance. Unfortunately
patients do not realize that the medication prevents far more fractures than it
causes. Even prescribing physicians fear to do more harm than good, which may
result in undertreatment. The occurrence of these atypical fractures is one of
the reasons that most guidelines advise not to treat patients with
bisphosphonates for more than five years unless there are strong reasons to
continue.

Patients* characteristics
Since bisphosphonates have been widely shown to prevent fractures, there must
be individual patients* characteristics predisposing them to such an event.
Besides, many patients with skeletal malignancies receiving massive doses of
bisphosphonates never develop AFFs, and some patients with AFFs have never used
bisphosphonates. Therefore it is plausible that factors other than
bisphosphonate use contribute to the AFF.
So far these characteristics or risk factors have not been ensured. Use of
co-medication such as glucocorticoids or proton-pump inhibitors was found to be
associated with AFFs in some, but not all studies. In a systematic review
amongst 141 cases of AFF, nearly 4 in 10 Caucasian women had used
glucocorticoids. Other striking features are the relatively young age, the high
number of comorbidities and non-osteoporotic bone densities described in
several studies. Also, ethnicity appears to be a relevant factor. Patients of
Asian descent are over-represented in some studies and AFFs may occur after a
considerably shorter duration of bisphosphonates in these patients. More
research is needed to identify clinical risk factors.

Genetic predisposition and femur shape analysis
Although some of the radiological features of AFFs resemble stress fractures,
they appear to have their origin in the lateral cortex suggesting that they
represent tensile failures of cortical bone. This may be caused by alterations
to the normal pattern of collagen cross-linking. The frequent bilateral
incidence of AFFs at the exact same anatomical location strongly suggests a
mechanical etiology potentially related to the shape of the femur or
systemic/structural bone pathology, factors that may have genetic influences. A
genetic susceptibility to AFFs is also likely since various inherited metabolic
bone diseases have been associated with AFFs, including X-linked
hypophosphatemia, hypophosphatasia, osteopetrosis, and pycnodysostosis and
Osteogenesis Imperfecta. We therefore propose that - more in general - patients
who develop AFFs on bisphosphonates have an underlying genetic predisposition
based on local biomechanical features related to femur shape or bone structure.
Many experts in the field have stressed the importance to identify underlying
causes, but so far most studies have been limited to case reports and
observational data. No studies have been performed using a thorough
genetic/genomic evaluation and in depth phenotyping with femur shape analysis.
Femur morphology and lower limb alignment can be evaluated with medical images
already available from patient files (DEXA, CT-scah, long leg X-ray).

Primary Objective: to identify risk factors and the underlying mechanism of
AFFs by:
- setting up a database with detailed information to define patients*
characteristics.
- building a biobank with urine and blood samples from these patients.
- performing genetic/genomic studies in blood from these patients.

We will address these questions below:
- How is a patient with high risk at atypical femur fractures identified?
- Do our findings on patients' characteristics correspond with previous
findings in medical literature?
- Does a genetic predisposition exist for atypical femur fractures?

The American Society for Bone and Mineral Research, among others, has
emphasized the importance of furhter research on clinical risk factors for
atypical femur fractures. A database with detailed information on patients*
characteristics and genetic analysis on these patients will hopefully define
risk factors and help us understand the underlying mechanisms of AFFs. Moreover
a genetic analysis amongst these patients has not been performed yet in the
area of medical research. This knowledge empowers medical specialists to
individualize decisions on whether or not to continue bisphosphonate treatment,
based on patients* risks and benefits. Confidence will be restored in treatment
with bisphosphonates, compliance will increase and more fractures will be
prevented. Based on the large number of patients with osteoporosis (estimated
800.000 in the Netherlands) this will lead to a substantial decrease in direct
and indirect health costs, morbidity and mortality
The biobank and database will be a basis for national and international
collaboration. The biobank provides blood and urine samples and thus
facilitates further research, especially if new insights and/or diagnostic
techniques become available.

The investigator determines whether a patient meets the inclusion criteria. A
radiologist will be consulted if necessary. After written consent has been
obtained, blood is drawn and subjects are requested to collect a first morning
urine sample. The samples are used for biobanking and (exome) sequencing. Tests
for bone turnover markers are performed only when these values have not been
determined yet during routine analyses. Extensive information on a large number
of variables is gathered, such as medical and family history, complete physical
examination, co-morbidities, medication use and medical imaging (assessment of
vertebral fractures). Also laboratory tests including bone turnover markers,
vitamin D levels, liver and kidney function and bone density scores by DXA.
Patient files are retrospectively viewed to obtain these data. Furthermore,
questionnaires are used to obtain missing information. In case important data
are lacking, the general practitioner or treating physician is contacted for
further requirements. Some data are used to describe the study population and
are not used for the primary outcome, though may be used for future further
analyses.

This inventory is drawn up in cooperation with several hospitals in the
Netherlands. Data are collected by researchers from Erasmus MC. Samples are
stored in the Genetic Laboratory of Internal Medicine, Erasmus MC. The expected
duration of this study is three years.

Patients* characteristics are described and compared to previous findings in
the medical literature and - if possible - to the mean values in the Dutch
population. Data from patients, such as bone density scores and medication use,
are compared to sex- and age-matched controls from the ERGO study. Participants
that use bisphosphonates will be matched with controls that use bisphosphonates
as well.
A case-control study is carried out to compare genetic profiles between
patients with AFF and 200 sex- and age-matched controls from the ERGO study.
The genetic analysis takes place in the Genetic Laboratory of the department of
Internal Medicine of Erasmus MC. For validation of genetic findings, we expect
to use at least 200 cases identified in independent populations from the
international osteoporosis consortia (GEFOS/GENOMOS).

For subjects involved there is no expected direct benefit. Questionnaires take
approximately 20 minutes. Laboratory tests are done on a regular basis as part
of the routine check for all subjects, hence the extra blood tubes and urine
samples needed in this study are a minimal burden. Participation is risk-free
or risks can be considered negligible, as one extra venipuncture is the only
invasive procedure in this study. Preferably we will extract extra tubes of
blood when subjects are at the hospital for regular monitoring. In this case,
no extra venipuncture is necessary. Incapacitated adults are also included in
this study, as AFF is a very rare complication and every single case of AFF is
a valuable source of information.