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ORIGINAL ARTICLE
Effectiveness of antiresorptive agents in the prevention
of recurrent hip fractures
S. Morin & E. Rahme & H. Behlouli & A. Tenenhouse &
D. Goltzman & L. Pilote
Received: 19 March 2007 / Accepted: 13 June 2007 / Published online: 19 July 2007
#
International Osteoporosis Foundation and National Osteoporosis Foundation 2007
Abstract
Summary Hip fracture is associated with recurrent fractures
and increased mortality. The results of our retrospective
cohort study support the use of antiresorptive agents to
prevent recurrent hip fractures in this population.
Introduction Hip fracture, the most serious consequence of
osteoporosis, is associated with recurr ent fractures and
increased mortality. Antiresorptive therapy has proven efficacy
in the prevention of fractures after vertebral fractures. It is
unknown if it can prevent recurrent fractures after a hip fracture.
Methods We designed a population based, retrospective
cohort study, using administrative databases and identified
patients hospitalized for a hip fracture between 1996 and
2002. The exposure was defined as being dispensed a
prescription for an antiresorptive agent at any time following
discharge. Multivariate Cox regression models were used to
estimate the hazard ratio of recurrent hip fracture. Subgroup
and propensity score analyses were performed.
Results A total of 20,644 patients were identified; 6,779 filled
a prescription for antiresorptive agents. There were 992
recurrent hip fractures. Patients exposed to antiresorptives
had a 26% reduction in the rate of recurrent fractures (adjusted
hazard ratio 0.74; 95% CI, 0.64–0.86) compared to patients
who were not. All subgroups experienced a reduction in
recurrent fracture, except the very elderly. Propensity score
analyses were consistent with the main analysis.
Conclusions Antiresorptive therapy reduces the risk of
recurrent hip fractures in elderly patients. These results
provide evidence that this therapy should be considered for
secondary prevention of hip fractures.
Keywords Antiresorptive agents
.
Hip fracture
.
Observational study
.
Osteoporosis
Osteoporosis is a disease characterized by quantitative and
qualitative changes of bone [1]. In the United States, ten
million individuals over age 50 suffer from osteoporosis
and 34 million more are at risk. Each year an estimated 1.5
million Americans suffer an osteoporotic-related fracture;
women are affected in 80% of the cases [2]. Hip fracture is
the most serious consequence of osteoporosis. It is
associated with a doubling in the relative risk of recurrent
fractures and excess mortality rate of 25% and higher,
compared to sex- and age-matched individuals [3–7].
In randomized controlled trials, several therapies have
documented efficacy in primary and secondary prevention
of ost eopor osis -rel ated vertebral fractures and p rimar y
prevention of non-vertebral fractures. Calcium and vitamin
D supplementation has been associated with a reduction in
non-vertebral fractures, including the hip, in institutional-
ized elderly persons and with a decreased risk of falls [8, 9].
Antiresorptive agents include hormone replacement therapy
(HRT), bisphosphonates, selective estrogen receptor mod-
Osteoporos Int (2007) 18:1625–1632
DOI 10.1007/s00198-007-0421-1
Dr. Morin is a Canadian Institutes of Health Research Bone Scholar,
Dr. Pilote is funded by the Canadian Institutes of Health Research.
Dr. Pilote is a William Dawson Professor of Medicine at McGill
University. This study was supported in part by a grant from the
Canadian Institutes of Health Research (#ATF-66669).
S. Morin (*)
:
E. Rahme
:
H. Behlouli
:
A. Tenenhouse
:
D. Goltzman
:
L. Pilote
Division of Internal Medicine,
McGill University Health Center (MUHC),
1650 Cedar Ave, Room B2-118,
Montreal, QC H3G 1A4, Canada
e-mail: suzanne.morin@mcgill.ca
S. Morin
:
E. Rahme
:
H. Behlouli
:
A. Tenenhouse
:
D. Goltzman
:
L. Pilote
Clinical Epidemiology, the Research Institute of the McGill
University Health Center,
1650 Cedar Ave, Room B2-118,
Montreal, QC H3G 1A4, Canada
ulators and calcitonin; they have been studied in diverse
populations of women with osteoporosis and to lesser
extent in men. Their anti-fracture efficacy ranges between
30–65% for new and recurrent vertebral fractures, depend-
ing on the agent and the population studied [10]. Clinical
trials have demonstrated reductions in the risk of a first hip
fracture with HRT (34%) and with bisphosphonates (27–
49%) in postmenopausal women [11, 12]. Alendronate and
risedronate also reduced vertebral fractures in osteoporotic
men but data on hip fracture among men are lacking [13,
14]. Obs ervational studies have documented effectiveness
of antiresorptive agents in reducing fractures in patients
identified in medical and pharmacy claims; however, it is
usually unknown if the patients are receiving treatment for
primary or secondary prevention of fractures [15, 16].
Further, there are no data on whether these medications are
effective when used after a hip fracture.
Despite insufficient data to support secondary prevention
of non-vertebral fractures, most osteoporosis-management
clinical guidelines advocate initiation of pharmacological
therapy in patients with any prevalent osteoporosis-related
fractures that confer a high risk of recurrence [17, 18]. It is
unknown, however, if any pharmacological therapy is
effective in preventing recurrent fracture in individuals
who have sustained a hip fracture.
The objectives of this study were to describe the patterns
of use of antiresorptive agents in older individuals from
1996 to 2002, and to determine their effectiveness in
preventing recurrent hip fractures.
Methods
Study design and population
We designed a retrospective cohort study of men and
women hospitalized for a hip fracture between 1996 and
2002, using the province of Quebec (Canada) hospital
discharge summary and the physician and drug claims
databases.The hospital discharge summary database pro-
vides information on hospital admissions for the entire
province including discharge diagnosis, up to 15 secondary
diagnoses, length of stay, discharge destination and in-
hospital mortality. The physician and drug claim database
provides information on all in- and out-patient diagnostic
and therapeutic procedures and physicians visits, out-of-
hospital mortality, as well as drug prescriptions for all
persons aged 65 years and older. The two databases were
merged using encrypted health insurance numbers. These
databases have been the source of many published epidemi-
ological studies. Information on vital status provided in these
databases has been shown to be accurate [19].
We identified all patients 65 years and older who were
discharged from hospital with a discharge diagnosis of hip
fracture (International Classification of Diseases, Ninth
revision (ICD-9) code 820.x) between April 1, 1996 and
March 31, 2002. We included all patients discharged from
acute care hospitals and rehabilitation centers. We excluded
patients with duplicate records (indicating a transfer
between institutions for the same episode of fracture) and
patients discharged to long-term care facilities because their
medications are not available in the provincial drug claim
database. The accuracy of these databases for the coding of
hip fractures, co-morbidities and prescription claims has
been shown to be high [20, 21].
The drug claim database was used to determine exposure to
medications. We considered the following medications as
antiresorptive agents: etidronate, alendronate, risedronate,
raloxifene, calcitonin (subcutaneous and nasal spray), and
hormone replacement therapy (HRT). All doses were consid-
ered. Alendronate was included on the provincial formulary in
1997; raloxifene, calcitonin by nasal spray and risedronate in
2000. Access to these medications is unrestricted in Quebec.
Calcium and Vitamin D supplements are available over the
counter, but can also be obtained by prescription.
Exposure
We defined as exposed those individuals who filled at least
one prescription for any antiresorptive agent at any point
during their follow up after discharge from the acute care
hospital or rehabilitation center; provided this prescription
occurred prior to a recurrent fracture.
Non-exposed individuals were categorized as such if
they never received a prescription for antiresorptive agents
during the follow up period or, if they received it after a
recurrent fracture.
Outcome
Recurrent fractures were defined as incident hip fractures
(ICD-9 code 820.x) requiring hospital readmission during
the observation period. We chose recurrent hip fractures as
a primary outcome, as opposed to all fractures, to ensure
completeness of ascertainment (nearly all hip fractures
require hospital admission) and because 90% of docu-
mented recurrent fractures in our cohort were of the hip.
Length of observation
Patients were followed until the first one of these events:
occurrence of a recurrent fracture, death or March 31, 2003
(providing at least one year of observation for patients who
were admitted with a hip fracture in 2002). We followed
1626 Osteoporos Int (2007) 18:1625–1632
exposed patients starting at the time of the filling of the first
prescription (time 0). To reduce the potential of survival
bias in favour of the exposed, the non-exposed patients
were assigned starting dates that were frequency matched to
those of the exposed; where the overall distribution of time
0 of the non-exposed is matched to that of the exposed [22].
The non-exposed, assigned a time 0 after a study outcome
had already occurred, were excluded from the analysis.
Covariates
Confounders known to affect fracture risk were identified
from the literature [23, 24]. To control for confounding in
subsequent analyses, the following variables were defined at
the time of the initial admission to hospital (available in the
hospital discharge database) : age, sex, co-medications (oral
corticosteroids, thiazide diuretics, calcium and vitamin D
supplementation; shown to affect fracture risk [25]), and
comorbidities (hypertension, cardiovascular diseases, chronic
lung disease, diabetes, dementia, malignancy, osteoporosis,
neurological diseases, renal dysfunction and rheumatologic
diseases). Comorbidities have been associated with increased
risks of falls and fragility fractures [26–28]. A comorbidity
index score (Charlson Index score as modified by Romano
for use in administrative databases) was derived for each
patient [29]. We defined length of stay as the time (days)
spent in the acute care hospital and in the rehabilitation
center prior to discharge home. Calendar year was included
in all analyses to control for temporal trends in prescription
of antiresorptive agents and supplements.
Because confounding variables were not distributed equally
amongst the two groups of patients, the effect of antiresorptive
agents was then compared in subgroups of patients who shared
similar baseline characteristics. We stratified the cohort based
on the presence or absence of comorbidities as defined by the
Charlson Index score (score of 0 or score >0).
Studies have shown that the efficacy of anti-osteoporotic
medications may vary with age, being less with increasing
age [30]. We chose to examine the effect of therapy after
stratifying the cohort based on age group (<80 years, ≥
80 years).
Increased mortali ty rates, highest in the first year
following a hip fracture, constitute an important competing
risk for the occurrence of recurrent fractures [4]. Therefore,
we also conducted the analysis in patients who survived the
first year after their discharge to the community, indicative
of a healthier subgro up.
Persistence with treatment has been found to be low in
post-menopausal women with osteoporosis and associated
with increased fracture risk [16, 17]. We evaluated the
dose-response relationship by analysing the re-fracture rates
in two subgroups of pat ients with different levels of
persistence with therapy. We defined persistence with therapy
as the cumulative days of use of an agent, consecutive or not,
over the first complete year of follow up (number of days on
medication/ 365 days×100) [31]. We identified individuals
with a high persistence as those who used an antiresorptive
agent for 80% of the time or more, during that year.
Propensity scores are used in observational studies to
estimate one’s conditional probability of a particular exposure
versus another, given observed confounders. Patients with
similar propensity scores have similar characteristics and
probability of exposure. This type of analysis permits the
evaluation of the effect of exposure in groups with similar
baseline characteristics, analogous to the intent of a random-
ized trial [32]. The success of the propensity score is judged
by confirming that, balance on pre-treatment characteristics
has been achieved between the treatment groups. Stratifica-
tion adjustment using the propensity score can then be used
to produce an unbiased estimate of the treatment effects [33].
To assess the robustness of our main analysis, we assessed
the treatment effect of antiresorptives after stratifying our
cohort on propensity score.
Statistical analysis
Multivariate Cox proportional models were used to estimate
the hazard ratio of recurrent hip fractures in the exposed and
non-exposed, after adjustment for potential differences in
baseline covariates. All potential confounders listed above
were simultaneously included in the model.
Analyses were also performed, using the same models, in
predefined subgroups: according to the presence or absence of
comorbidities, in different age groups (<80 years, ≥80 years)
and in patients who survived the first year after the initial
fracture.
Propensity scores were obtained in logistic regression
models. The selection of variables to be included in the model
was based on forward selection and the model checked against
a model based on backward selection. We divided the cohort
in quintiles of propensity scores and examined the risk of re-
fracture in each quintile.
All analyses were performed using the statistical software
SAS version 9.1 (SAS Institute, Cary, North Carolina). A P
value of less than 0.05 was considered statistically significant
for all analyses.
Ethical considerations
All the data used for the analyses were anonymous and
confidential; personal ident ifiers were encrypted by the
governmental agency prior to receiving the data. The McGill
University Institutional Review Board approved this study.
Osteoporos Int (2007) 18:1625–1632 1627
Results
In total, 30,634 patients were admitted to hospital following
a hip fracture between 1996 and 2002 .After exclusions of
patients who did not survive to discharge (3,382) and who
were discharged to a long-term care institution (6,608), a
cohort of 20,644 patients was identified; 6,779 filled a
prescription for antiresorptive agents (exposed). In general,
exposed patients were younger and had less comorbidity
than non-exposed patients (Table 1). Women comprised
80% of the cohort and were 81 [SD 7] years old on average.
Men were younger (mean age 78 [SD 8] years), had more
comorbidity and were less like ly to receive antiresorptive
therapy. Median time to first prescription was 85 days
(interquartile range 11–395). Mean time of follow up was
2.15 [SD 1.6] years for the exposed and 2.24 [1.7] years for
the non-exposed. During this time, there were 992 recurrent
hip fractures and 9146 deaths.
Prescriptions for antiresorptive agents increased during
the study period as agents became available; by 2002,
bisphosphonates were the agents prescribed most frequently
(Fig. 1). Median duration of therapy was 317 d ays
(interquartile range 90–729). Among exposed patients, the
cumulative proportions who received a prescription for any
agent 30, 90 and 365 days following discharge were
respectively: 35, 51 and 74%.
The rate of recurrent fracture was 2.17 per 100 person-
years in the exposed group and 2.90 per 100 person-years
in the non-exposed group (crude rate ratio 0.75; 95% CI
0.65–0.86). In adjusted multi variable models, subjects
exposed to antiresorptive agents experienced a reduction
in the rate of recurrent hip fracture of 26% (HR 0.74; 95%
CI 0.64–0.86) (Table 2).
After adjusting for baseline covariates, exposure was
associated with a decrease in the risk of recurrent fracture in
patients with and without comorbidities (HR 0.71; 95% CI
0.59–0.86 and HR 0.80; 95% CI 0.64–1.00, respectively)
(Fig. 2). The largest benefit of exposure was observed in
the subgroup of patients 80 years and younger as their risk
of recurrent fracture was almost half of that of the non-
exposed (HR 0.53; 95% CI 0.42–0.67). We were unable to
show a positive effect of exposure in the older age group
(HR 0.92; 95% CI 0.77–1.10). The interaction between
exposure to antiresorptives and age was significant (p=
0.02) suggesting that the effect of treatment varied with
age. In patients who survived the first year after disch arge,
results were consistent with the main analysis (HR, 0.82;
95% CI 0.68–0.97).
In patients who persisted with therapy 80% of the time
or more, exposure was associated with a reduction in
recurrent of fractures of 3 4% (crude rate ratio 0.66; 95% CI
0.52–0.84) when compared with patients who were less
persistent.
Finally, our propensity score model predicted exposure
to antiresorptive agents (C statistic=0.725) and adequately
balanced the co nfounders between the two exp osure
groups. Using our proportionate multivariable model, we
repeated the analysis in each quintile of propensity score
and confirmed that the risk of recurrent fracture was
reduced in the exposed compared to the non-exposed, in
the four quintiles where there were enough patients exposed
to antiresorptive agents (Fig. 3).
Discussion
In this large popula tion of elderly patients with a major
fragility fracture, exposure to antiresorptive therapy reduced
recurrent hip fractures. It is the first time that effectiveness
of therapy is evaluated in this population. We showed that
all subgroups, except the very elderly, benefited from
Table 1 Baseline characteristics of subjects, by exposure status
Antiresorptive
therapy
No
therapy
(N=6779) (N=13865)
Mean age (SD), years 79 (7) 81 (8)
Age groups, (%)
65–69 years 11 8
70–74 years 17 13
75–79 years 24 20
≥80 years 48 60
Women, (%) 90 73
Co-morbidities, (%)
a
Hypertension 39 35
Chronic obstructive lung disease 16 16
Diabetes 11 15
Dementia 4 14
Neurological disease 8 11
Congestive heart failure 5 8
Myocardial infarction 4 5
Renal failure 2 5
Rheumatologic disease 4 1
Malignancy 3 4
Osteoporosis 1 0
Median Charlson index
b
(IQR) 0 (0, 2) 1 (0, 3)
Medication at discharge, (%) 12 3
Calcium supplement 12 3
Vitamin D supplement 10 3
Oral corticosteroid 3 3
Thiazide diuretic 27 17
Median length of stay
c
(IQR), days 34 (16, 53) 30 (13, 52)
IQR- interquartile range
a
As documented by physicians in the hospital discharge database.
b
Romano’s adaptation of the Charlson Index for use with claims
databases.
c
Length of stay in both acute care hospital and rehabilitation center.
1628 Osteoporos Int (2007) 18:1625–1632
treatment; although the overall risk reduction was less than
that documented in randomized trials. The larger benefits
noted in these studies might be explained by the systematic
use of calcium and Vitamin D by the participants as well as
younger age, absence of comorbidities and homogeneity of
the study populations [10]. Nonetheless, we have docu-
mented reductions in risk of hip fracture in the subgroups of
patients without any co-morbidity and patients 80 years of
age and less, comparable to participants of clinical trials.
The lack of effect of therapy in the older age group may
be explained in part by the following factors. Vitamin D
insufficiency is highly prevalent in elderly patients with hip
fractures [34]. It is responsible for accelerated bone loss and
increased risk for fractures [35]. In vitamin D insufficient
patients, therapeutic response to antiresorptive agents is less
than that demonstrated in clinical trials [36]. Non-skeletal
factors such as fall patterns may dictate the risk for
fractures, regardless of therapy. Post hoc analyses of older
subgroups (80 years and older) of wom en in randomized
trials have shown benefits of risedronate in reducing
recurrent verteb ral, but not non-vertebral fractures [30].
Although not documented with raloxifene or calcitonin, this
differential therapeutic effect deserves future investigation.
Antiresorptive agents rapidly reduce bone remodelling.
This leads to increased bone strength and reduced fracture
risk within a year of initiating therapy [37, 38]. Such
efficacy is essential because patients with a recent osteo-
porosis-fracture have a high incidence of recurrence in the
year following the initial event, as seen in our cohort [39].
In patients who survived the first year after discharge from
the hospital experienced an 18% reduction in the risk of re-
fracture after exposure to antiresorptive therapy.
Persistence with therapy improves outcomes [40]. In our
study, individuals who persisted longer with treatment had
a larger reduction in the risk for recurrent fracture. Our
method of assessment of persistence has been used in other
studies and shown to be accurate; however, because of the
number of different medications and doses evaluated in our
cohort we were unable to evaluate the effect of persistence
to individual agents [31 ].
Few patients received a prescription for calcium and
vitamin D supplements upon discharge; this has been
recorded previously [41]. These supplements are available
without prescription; there fore, their dispensations are not
recorded in databases and unavailable for inclusion in our
analyses. It is possible, that part of the effect seen in the
patients exposed to antiresorptive be secondary to a higher
usage of calcium and vitamin D as they have been
associated with lower risk of hip fractures in elderly
individuals [9]. However, data from randomized trials have
shown that in patients at high risk of re-fracture, calcium
and vitamin D supplementation, as used in the placebo
groups, was not sufficient to prevent recurrences.
We also did n ot have information on whether bone
mineral density (BMD) measurements were performed.
BMD has been shown to be correlated with fracture risk
0
5
10
15
20
25
30
35
1996 1997 1998 1999 2000 2001 2002
Bisphosphonates
Hormonal therapy
Calcitonin
Raloxifene
% of
Patients
Fig. 1 Temporal trends in the
proportion of patients who fill
prescriptions for antiresorptive
agents between 1996 and 2002
Table 2 Effectiveness of antiresorptive agents in preventing recurrent
hip fractures
a
Hazard ratio 95% CI
Antiresorptive therapy 0.74 (0.64–0.86)
Sex
b
0.75 (0.63–0.90)
Age
c
1.03 (1.02–1.04)
Osteoporosis
d
2.32 (1.15–4.65)
a
Model is adjusted for age, sex, baseline characteristics and calendar
year.
b
Men compared to women.
c
For each additional year of age.
d
As documented by physicians in the hospital discharge database.
Osteoporos Int (2007) 18:1625–1632 1629
and known to influence initiation of therapy when measure-
ments are available [42]. Although BMD is measured in
less than 15% of patients following a hip fracture, there
may have been differential assessment of BMD between the
groups [41]. A possible scenario would be that, screened
patients would be found to have a BMD result diagnostic of
osteoporosis and encourage the clinician to prescribe
antiresorptive therapy. This would, however, tend to
increase the proportion of patients with more severe disease
in the exposed group.
Unmeasured confounders may, in part ex plain our
findings. We had limited data on clinical indicators of
frailty and risk for falls. Risk factors that have been
strongly associated with falls include age, cognitive
impairment, the presence of two or more chronic con-
ditions, low body mass and gait impairment [43]. We were
able to adjust for many of these factors in our analysis and
feel that imbalances in the distribution of these unmeasured
confounders did not account for the results found in the
analyses.
Because of limited numbers of patients per class of
antiresorptive agents we could not analyse the effect of one
agent versus another, such as has been done in other
analyses to reduce confounding [15, 44]. Thus, on the
whole, our adjusted results support the effectiveness of
antiresorptive therapy in the prevent ion of recurrent hip
fractures.
Finally, patients discharged to long-term care were
excluded from the analysis because their prescription
records are unavailable in the databases. Such patients are
frail, have higher mortality rates and are less likely to
receive antiresorptive therapy [45]. Their presence in the
cohort would have increased the proportion of unexposed
patients and would have been unlikely to change the
direction of the results of the analyses.
Despite these limitations, an observational study design
has the undisputed advantage of obtaining data on a large
population of patients that otherwise would not be
accessible. Randomized clinical trials are difficult to carry
out in frail elderly patients. Therefore, results of observa-
tional studies, such as the one we have conducted, add to
the body of knowledge collected from previous clinical
trials and quantify the effectiveness of treatment in real
world practice.
At least 300,000 hip fractures occur in the United States
every year and this figure will rise over the next decade [2].
Although 90% of fractures are related to falls, interventions
that decrease the risk of falling have had a modest impact
on the reductions of fractures [46, 47]. Consequently,
All Patients
Without comorbidities
With comorbidities
Age group < 80 years
Age group
≤
≤
80 years
Patients who survive
1
st
year after discharge
0.74 (0.64-0.85)
0.71 (0.59-0.86)
0.80 (0.64-1.00)
0.53 (0.42-0.67)
0.92 (0.77-1.10)
0.82 (0.68-0.97)
0 0.5 1 1.5 2.0
Adjusted Hazard Ratios (95% Confidence Intervals)
Fig. 2 Risk of Recurrent Hip
Fracture in Subgroups
0 0.5 1 1.5 2.0
Main analysis
Quintile 1
Quintile 2
Quintile 3
Quintile 4
Quintile 5
2,4024,119
1,7784,181
1,3614,083
7824,130
4564,131
6,77920,644
N Expose
d
Hazard Ratio (95% Confidence Intervals)
Fig. 3 Risk of recurrent hip fracture by propensity score quintile (Q1
to Q5)
1630 Osteoporos Int (2007) 18:1625–1632
efforts to rapidly increase bone strength through pha rma-
cological modalities have been extensive.
Our data s upports, for the first time, the u se of
antiresorptive agents for the redu ct ion of the ri sk of
recurrent fractures in patients after a hip fracture.
Acknowledgements This study was funded in part by grant #ATF
6669 from the Canadian Institutes of Health Research. Dr. Morin is a
scholar of the CIHR Skeletal Health Training Program. The funding
agency had no role in the design of the study, in the collection,
analysis and interpretation of the data, in the writing of the manuscript
and in the decision to submit the paper for publication.
Conflict of interest statement Dr. Morin has received honoraria
(consultant and speaker fees) from the Alliance for Better Bone
Health, Merck and Eli Lilly. Dr. Rahme has received grants and
consultant fees from Merck, Pfizer and Boehringer Ingelheim. All
other authors have no conflict of interest.
Author_s contributions:
Drs Morin and Pilote were responsible for the conception of the
study.
Dr. Pilote was responsible for acquisition of the data.
Drs. Morin and Behlouli were responsible for the data programming.
Drs. Morin, Pilote, Rahme, Behlouli and Goltzman were responsible
for the design of the study, data analysis and interpretation.
Dr. Morin was responsible for writing the manuscript.
All authors were responsible for revising the manuscript critically
for important intellectual content.
All authors have seen and approved the final version of the
manuscript.
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