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Wang PS, Solomon DH, Mogun H, Avorn J. HMG-CoA Reductase Inhibitors and the Risk of Hip Fractures in Elderly Patients. JAMA. 2000;283(24):3211–3216. doi:10.1001/jama.283.24.3211
Author Affiliations: Program for the Analysis of Clinical Strategies, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass.
Context Recent animal studies have found that 3-hydroxy-3-methylglutaryl coenzyme
A (HMG-CoA) lipid-lowering drugs (statins) substantially increase bone formation,
but whether statin use in humans results in clinically meaningful bone formation
or a reduction in the risk of osteoporotic fractures is not known.
Objective To determine whether the use of statins is associated with reduced hip
Design Case-control study.
Setting and Patients A total of 6110 New Jersey residents aged 65 years or older and enrolled
in Medicare and either Medicaid or the Pharmacy Assistance for the Aged and
Disabled program. Case patients (n=1222) underwent surgical repair of a hip
fracture in 1994. Control patients (n=4888) were identified at a ratio of
4:1 and frequency-matched to case patients for age and sex.
Main Outcome Measure Adjusted odds ratio (OR) of hip fracture by statin use in the 180 days
and 3 years prior to the index date (the earliest date of admission for surgery),
adjusted for demographic and clinical characteristics and health care utilization.
Results Use of statins in either the prior 180 days (adjusted OR, 0.50; 95%
confidence interval [CI], 0.33-0.76) or prior 3 years (adjusted OR, 0.57;
95% CI, 0.40-0.82) was associated with a significant reduction in the risk
of hip fracture, even after controlling for variables such as race, insurance
status, psychoactive medications, estrogen and thiazide use, ischemic heart
disease, cancer, and diabetes mellitus. No significant relationship was observed
between use of nonstatin lipid-lowering agents and hip fracture risk. Clear
relationships were observed between the degree of reduction in hip fracture
risk and the extent of statin use; there was no evidence of such relationships
with nonstatin lipid-lowering agents. After adjusting for extent of statin
use in the prior 3 years, current use (on the index date) was associated with
a 71% reduction in risk (adjusted OR, 0.29; 95% CI, 0.10-0.81). The relationship
between statin use and hip fracture risk persisted after controlling for variables
such as the number of medications, the Charlson comorbidity index score, and
hospitalization or nursing home stay in the last 180 days, as well as after
excluding patients who were in a nursing home prior to their index date or
who died in the year after their index date. Use of nonstatin lipid-lowering
agents was not observed to be associated with reduction in hip fracture risk
in any of these alternative models or analyses.
Conclusions These findings support an association between statin use by elderly
patients and reduction in the risk of hip fracture. Controlled trials are
needed to exclude the possibility of unmeasured confounders.
Osteoporosis affects 20% of women older than 50 years and an even larger
proportion of elderly women; fractures attributable to osteoporosis occur
in approximately 1.5 million Americans annually.1-3
Although several recently approved medications effectively prevent and treat
osteoporosis, no currently approved drug has been shown to stimulate bone
formation activity by osteoblasts.4
A recent report suggests that drugs inhibiting 3-hydroxy-3-methylglutaryl
coenzyme A reductase (HMG-CoA) (statins), commonly used to lower lipid levels,
may have such potential.5 Oophorectomized rats
given statins in oral dosages comparable to those used in humans (ie, 1-10
mg/kg per day of simvastatin) had a 40% to 90% increase in the trabecular
bone volume of the femur and lumbar vertebrae within 35 days, relative to
rats given placebo. Statins appear to enhance osteoblast activity through
increasing expression of the bone morphogenetic protein 2, a stimulator of
osteoblast differentiation. Statins also may be linked to bone metabolism
through their ability to inhibit mevalonate synthesis, a mechanism shared
with several bisphosphonates.6 Mevalonate is
a precursor necessary for production of cholesterol and 2 lipoids important
in the control of osteoclast activity. However, it is not yet clear whether
these in vitro and animal findings have clinically useful implications for
patient care. Another recent report7 found
that statin use in humans may result in increased bone mineral density. However,
it was not evident whether such increases are clinically meaningful or result
in a reduction in osteoporotic fractures.
While many randomized controlled trials have been performed to test
the efficacy of statins in reducing coronary heart disease, fracture outcomes
have not been reported, and older patients who would be most likely to demonstrate
this effect generally have been excluded.8,9
One recent report from an observational study identified a statistically nonsignificant
decrease in the relative risk of hip fracture for users of statins but not
in users of nonstatin lipid-lowering drugs.10
We examined whether statin use is associated with a reduction in hip fracture
rates by analyzing a database containing information on all filled prescriptions,
hospital care, surgical procedures, and physician visits for a very large
population of older patients.
New Jersey Medicaid Program. We extracted information on all individuals enrolled in the New Jersey
Medicaid program from January 1, 1991, to June 30, 1995, including demographic
information; dates of enrollment; outpatient, nursing home, and hospital utilization
data; and data for all filled prescriptions. The indigent status of Medicaid
enrollees results in essentially no out-of-system health care utilization
since such utilization would be an out-of-pocket expense.
New Jersey Pharmacy Assistance for the Aged and Disabled Program. Additional information on nonindigent patients, the vast majority of
whom are aged 65 years and older, was derived for the same time period from
the New Jersey Pharmacy Assistance for the Aged and Disabled (PAAD) program,
a state-specific program of reimbursement for the drug expenses of nonindigent
elderly and disabled citizens.
New Jersey Medicare. Medicare data used in the present study included both Medicare Part
A data on hospitalizations and nursing home stays, and Medicare Part B data
on services and procedures for essentially all New Jersey residents older
than 65 years.
We identified all Medicare beneficiaries who were also enrolled in either
Medicaid or PAAD (approximately 46%) because the latter 2 programs, but not
Medicare, provide comprehensive data on all prescriptions filled. All data
on each subject were assembled on a person-specific basis into a relational
database to integrate information on prescriptions, procedures, physician
encounters, hospitalizations, and long-term care for each individual. All
traceable person-specific identifiers were transformed into anonymous, coded
study numbers to protect the privacy of program participants.
The study population (Table 1)
consisted of all patients aged 65 years and older on July 1, 1993, who met
program use criteria described below. To ensure complete ascertainment of
health care utilization, all patients were required to have had at least 1
medical service during 1994 and to have filled at least 1 prescription for
any medication through the Medicaid or PAAD programs in each of 4 consecutive
6-month periods beginning January 1, 1993. We also identified patients who
filled 1 or more prescriptions in each of 4 consecutive 6-month periods beginning
January 1, 1991, for the analyses of 3-year drug use. Patients who had been
hospitalized in the month prior to the index date were excluded.
Cases of hip fracture were defined as any patient hospitalized between
January 1, 1994, and December 31, 1994, for surgical repair of a hip fracture
as reflected in a claim for this procedure by a surgeon.11,12
The index date for cases was the earliest date of admission for this surgery.
Four control patients were drawn at random from the study population for each
case patient, frequency matched to case patients by year of birth and sex.
Each control patient was randomly assigned an index date frequency matched
to the index dates of case patients. Case patients and controls were required
to have no diagnoses of hip fracture or evidence of hip fracture surgical
repairs prior to their index date.
Use of Lipid-Lowering Drugs in the 180 Days and 3 Years Prior to the
Index Date. Patients who filled any prescriptions for fluvastatin, lovastatin, pravastatin,
or simvastatin in the 180 days prior to their index date were considered to
have been exposed to a statin lipid-lowering drug. Patients who filled any
prescriptions for cholestyramine, clofibrate, colestipol, gemfibrozil, niacin,
or probucol in the 180 days prior to their index date were considered to have
been exposed to a nonstatin lipid-lowering agent. We also identified eligible
patients who used each of these drugs in the 3 years prior to their index
Extent of Lipid-Lowering Drug Use in the 180 Days and 3 Years Prior
to the Index Date. Using the quantity dispensed and days supply data recorded on prescriptions,
we calculated the number of days in the 180 days prior to the index date for
which each individual had a filled prescription for a statin drug or a nonstatin
lipid-lowering agent. Among eligible subjects, we also calculated the number
of such days covered in the 3 years prior to the index date. We used the distributions
of days covered to divide individuals exposed to statin and nonstatin lipid-lowering
drugs into 4 equal groups (quartiles).
The variables for all case and control patients used to calculate the
crude and adjusted odds ratios (ORs) were obtained as follows. Program enrollment
information was used to determine the sociodemographic characteristics of
age, sex, race, and insurance status (Medicaid vs PAAD). We determined other
specific medication use by examining all prescriptions filled in the 180 days
prior to the index date and recording use of estrogen replacement therapy,
oral corticosteroids, thiazide diuretics, or any psychoactive medication.
Additional drugs were studied as markers of specific clinical conditions.
We scanned all episodes of inpatient and outpatient care and filled prescription
data in the 180 days prior to the index date to identify evidence of the following
comorbidities: ischemic heart disease (based on diagnoses,11
procedures such as angioplasty or bypass surgery,11,12
hospitalization codes,13 and prescriptions
for nitrates); congestive heart failure (based on diagnostic codes and hospitalization
codes); hypertension (based on diagnoses and hospitalization codes); diabetes
mellitus (based on diagnoses, hospitalization codes, and prescriptions for
insulin or oral hypoglycemics); and cancer excluding nonmelanoma skin cancer
(based on diagnoses). We also used diagnostic information from all inpatient
and outpatient encounters in the 180 days prior to the index date to calculate
a modified Charlson comorbidity index score, a commonly used measure of the
extent of comorbid illness.14 Finally, we recorded
whether patients died in the 365 days following their index date.
The extent of health care utilization was assessed in the 180 days prior
to the index date as the number of medications (different generic entities)
used, days hospitalized, days spent in a nursing home, and physician visits.
We initially measured the demographic, clinical, and health care utilization
characteristics of case and control patients. Crude ORs of hip fracture were
then calculated for any statin use in the 180 days prior and in the 3 years
prior to the index date relative to no use. The statistical significance of
relationships was assessed using χ2 statistics and 95% confidence
We next constructed multivariable unconditional logistic regression
models of the risk of hip fracture using SAS, version 6.12 (SAS Institute,
Cary, NC) to control for possible confounding by patients' clinical or sociodemographic
characteristics. Variables representing the use of statins as well as nonstatin
lipid-lowering drugs (separately for the prior 180 days or the prior 3 years),
and estrogen replacement therapy were introduced into the model, as were age
and sex. Remaining covariates representing specific clinical conditions, other
medication use, and demographic characteristics were then subjected to a forward,
stepwise selection procedure with a selection criterion of P≤.20. To assess the robustness of the findings and test for the
possibility of other confounders, we then constructed alternative multivariable
models in which comorbid disease severity scores (categorized as 0, 1, and ≥2)
and health care utilization variables were subjected to a forward selection
To address the possibility that statins might be preferentially prescribed
to healthier patients (who would also be at lower risk of hip fracture), we
studied 2 subsamples of patients: one that excluded any individuals who were
in a nursing home in the 180 days prior to their index date and another that
excluded all those who died in the 365 days after the index date.
To examine whether the extent of use of lipid-lowering drugs was associated
with hip fracture risk, we measured hip fracture risk in relation to the number
of days of use of statin and nonstatin lipid-lowering drugs, as reflected
in the quantities dispensed in all filled prescriptions for these agents.
The adjusted risks associated with quartiles of use during the prior 180 days
as well as the 3 years prior to the index date were calculated. Finally, as
an additional test of the biological relevance of any statin–hip fracture
relationship, we examined the effect of current statin use (as of the index
date) in a model controlling for the extent of statin use in the previous
Characteristics of the study population (n = 1222 cases and n = 4888
controls) are presented in Table 1.
The patient population was mostly aged 75 years or older and female. In keeping
with previous findings,15-24
case patients were more likely than control patients to be white and users
of corticosteroids or psychoactive medications but less likely to be thiazide
users. Case patients were somewhat more likely than control patients to have
ischemic heart disease, diabetes mellitus, or cancer but were less likely
to have hypertension.
Table 2 presents the crude
and adjusted ORs from logistic regression models of factors associated with
the risk of hip fracture. In unadjusted analyses, statin use in the 180 days
prior to the index date was associated with a 50% reduction in hip fracture
risk. Controlling for a wide range of clinical variables, other medication
use, and demographic characteristics had essentially no effect on this finding,
with statin use in the prior 180 days still associated with a 50% reduction
in the risk of hip fracture (Figure 1).
By contrast, use of nonstatin lipid-lowering agents in the prior 180 days
did not have a statistically significant association with hip fracture rates
in either crude or multivariable analyses.
Statin use in the prior 3 years also was associated with a 43% reduction
in the crude and adjusted risk of hip fracture (Table 2 and Figure 1).
No significant associations were observed for use of nonstatin lipid-lowering
drugs over this period, despite a substantial increase in the number of subjects
exposed to these drugs. The model presented in Table 2 also supports other epidemiologic associations with hip
fracture reported in previous studies.15-24
In alternative models, statin use in both the prior 180 days and the
prior 3 years continued to be significantly associated with a reduction of
comparable magnitude in risk of hip fracture, while no significant associations
were observed between use of nonstatin lipid-lowering agents and hip fracture
risk. Table 3 presents results
of models containing comorbidity scores and health care utilization variables
rather than specific diagnoses, with essentially the same findings.
Additional analyses were conducted to adjust for the possibility that
statins may be preferentially withheld from frail patients or those in long-term
care facilities, who might also have higher fracture rates. The significant
association between statin use and reduction in hip fracture risk remained
virtually unchanged when the population studied was restricted to case and
control patients who had not been in a nursing home in the 180 days prior
to the index date (any statin use in 180 days prior vs no use: adjusted OR,
0.57; 95% CI, 0.37-0.87), as well as in a subgroup of patients restricted
to those who did not die in the year after the index date (adjusted OR, 0.45;
95% CI, 0.28-0.71).
If the relationship between statin use and fracture was causal, a greater
protective effect with greater use would be expected. After controlling for
the possible confounders described above, we observed a clear use-response
relationship when we examined the risk of hip fracture associated with quartiles
of statin use in the prior 180 days. Figure
2 presents the adjusted relative odds of hip fracture for quartiles
of days of statin use in the 3 years prior to the index date. It demonstrates
a clear use-response relationship between statin use and decrease in hip fracture
risk, with risk significantly reduced to 0.37 for the highest quartile of
use relative to no use (95% CI, 0.17-0.82). By contrast, there was no use-response
relationship for nonstatin lipid-lowering agents in either time period.
Finally, we determined the effect of current statin use (as of the index
date), as well as prior, but not current, statin use, from a model controlling
for total use over the previous 3 years. Current statin use was associated
with an even greater (71%) reduction in the risk of hip fracture (current
statin use vs no use: adjusted OR, 0.29; 95% CI, 0.10-0.81 [Figure 1]) while past use in the absence of current use did not
show a significant association (prior-only statin use vs no use: adjusted
OR, 0.60; 95% CI, 0.29-1.25), even after adjusting for total number of days
of use during the 3-year period.
In this study of 1222 elderly patients with hip fracture and 4888 controls,
the use of statin lipid-lowering medication was associated with a 50% reduction
in the risk of hip fracture, even after controlling for comorbidity, extent
of health care utilization, age, sex, race, and insurance status. Three findings
provide evidence that this relationship may be both causal and related to
the biological activity of statins. First, we did not observe any significant
protective effect for nonstatin lipid-lowering agents—a therapeutic
class with the same indications but with different underlying mechanisms of
action. Second, we observed clear use-response relationships between both
short-term (prior 180 days) and longer-term (prior 3 year) statin use and
reduction in hip fracture risk. This finding of a short-term use-response
relationship suggests that the protection conferred by statin use may begin
after a relatively short period and is consistent with the time frame in which
new bone formation has been shown to occur in both in vivo and in vitro rodent
models.5 Alternatively, extensive short-term
statin use in our study population also may have been a marker of patients
with more extensive long-term use. Finally, we observed the lowest risks with
current statin use rather than prior use, even after adjusting for the total
extent of statin use.
The fact that the medical community and patients were unaware of any
potential association between statin use and bone density in 1991-1994 and
the highly variable nature of the use of these drugs in older patients during
this period provided a good context in which to explore this relationship
retrospectively. However, it is important to consider several potential limitations
of this study and whether they could provide an alternative explanation for
First is the possibility that statins may have been given preferentially
to less frail patients or those otherwise at lower risk of hip fracture. However,
the approximately 50% reduction in risk did not change when we adjusted for
the presence of a wide variety of comorbid conditions, such as ischemic heart
disease, hypertension, congestive heart failure, diabetes mellitus, or cancer,
as well as for other measures of chronic illness such as days spent in hospital,
number of physician visits, Charlson comorbidity index score, number of medications
taken, nursing home residency, and death in the following year.
Another possibility is that statins were used preferentially in patients
(or prescribed by physicians) who might have been more "prevention-oriented";
such an orientation may in turn have been associated with a higher baseline
health status and/or use of other measures that would lower the risk of fracture.
In 1991-1994, apart from estrogen replacement therapy, use of other medications
specifically for osteoporosis was uncommon. Introduction into the multivariate
model of a variable describing the use of estrogen replacement therapy had
no effect on the statin–hip fracture relationship. Most importantly,
in no analysis did we observe a significant protective effect for nonstatin
lipid-lowering agents, which are prescribed for the same indications, including
analyses of use during the prior 3 years, which provided considerable additional
statistical power to observe a relationship if it were present.
Third, because we could not measure weight or body mass index in our
data, it is possible that obesity might be associated with both statin use
and a reduced risk of hip fracture. However, a recent observational study
by Bauer and colleagues10 did attempt to assess
the effect of statin use on hip fracture risk among 2 cohorts of elderly women
in whom data were available on body mass index, exercise history, smoking,
and other clinical characteristics. After controlling for these variables,
Bauer et al10 reported a reduction in the relative
risk of hip fracture among statin users, but these findings did not reach
statistical significance, perhaps because the number of fractures was too
small. In the present study, greater body mass index probably explains some
of the modest reduction in hip fracture rates seen among hypertensive patients;
controlling for the presence of hypertension in our analysis did not alter
the observed statin effect. The drug use data were based on filled prescription
claims rather than directly observed drug use, and the outcome assessment
was based on claims filed by surgeons for performing a surgical repair of
a hip fracture. It is conceivable that these assessments may have led to misclassification
in some instances,25 but it is not clear how
this would have introduced any systematic bias. Finally, it is possible that
some of the observed reduction in fracture risk may be attributable to prevention
of stroke and myocardial infarction, which, in theory, could have precipitated
falls resulting in fracture. However, this is unlikely to explain more than
a small fraction of the observed risk reduction, particularly since the reduction
in fracture rates was larger than the previously reported rates of reduction
in myocardial infarction or stroke events.
Despite these striking findings, it remains possible that some aspect
of physicians' selection of patients for statin therapy, unaddressed in the
present analysis, might confound the relationship observed. Future observational
studies or randomized trials will be required to address this possibility
and to further our understanding of the potential effects of statins in relation
to fractures in elderly patients.
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