Meier CR, Schlienger RG, Kraenzlin ME, Schlegel B, Jick H. HMG-CoA Reductase Inhibitors and the Risk of Fractures. JAMA. 2000;283(24):3205-3210. doi:10.1001/jama.283.24.3205
Author Affiliations: Basel Pharmacoepidemiology Unit, Division of Clinical Pharmacology (Drs Meier, Schlienger, and Schlegel), and Division of Endocrinology, Diabetes, and Clinical Nutrition (Dr Kraenzlin), University Hospital, and Institute of Pharmacotherapy, Department of Pharmacy, University of Basel (Dr Schlienger), Basel, Switzerland; and Boston Collaborative Drug Surveillance Program, Boston University, School of Medicine, Lexington, Mass (Drs Meier and Jick).
Context Recent animal studies have suggested that 3-hydroxy-3-methylglutaryl
coenzyme A (HMG-CoA) reductase inhibitors (statins) increase bone formation,
volume, and density. It is unknown whether use of statins is associated with
a decreased risk of fractures in humans.
Objective To determine whether exposure to statins, fibrates, or other lipid-lowering
drugs is associated with reduced bone fracture risk.
Design Population-based, nested case-control analysis.
Setting The UK-based General Practice Research Database (GPRD), comprising some
300 practices, with data collection from the late 1980s until September 1998.
Subjects Within a base population of 91,611 individuals aged at least 50 years
(28,340 individuals taking lipid-lowering drugs, 13,271 untreated individuals
with a diagnosis of hyperlipidemia, and 50,000 randomly selected individuals
without diagnosis of hyperlipidemia), we identified 3940 case patients who
had a bone fracture and 23,379 control patients matched for age (±5
years), sex, general practice attended, calendar year, and years since enrollment
in the GPRD.
Main Outcome Measures Use of statins, fibrates, or other lipid-lowering drugs in case patients
vs control patients.
Results After controlling for body mass index, smoking, number of physician
visits, and corticosteroid and estrogen use, current use of statins was associated
with a significantly reduced fracture risk (adjusted odds ratio [OR], 0.55;
95% confidence interval [CI], 0.44-0.69) compared with nonuse of lipid-lowering
drugs. Current use of fibrates or other lipid-lowering drugs was not related
to a significantly decreased bone fracture risk (adjusted OR, 0.87; 95% CI,
0.70-1.08 and adjusted OR, 0.76; 95% CI, 0.41-1.39, respectively).
Conclusions This study suggests that current exposure to statins is associated with
a decreased risk of bone fractures in individuals age 50 years and older.
This finding has a potentially important public health impact and should be
confirmed further in controlled prospective trials.
The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors
(statins) are effective in reducing the risk of cardiovascular morbidity and
mortality in patients with hyperlipidemia.1- 6
In addition to the ability of statins to decrease serum cholesterol levels,
recent studies in animals showed that these agents have pharmacologic effects
on bones. Mundy et al7 recently reported substantial
increases in bone formation and trabecular bone volume in female rats after
5 weeks of oral simvastatin administration. Additional animal studies indicated
that statins may decrease the severity of steroid-induced osteonecrosis.8,9
These results from animal studies were partly supported in a cross-sectional
study by Bauer et al10 in older women taking
lipid-lowering agents (mainly lovastatin). Preliminary results of this small
study suggested that statin use may be accompanied by increased hip bone mineral
density, thereby potentially lowering the risk of hip fractures. Furthermore,
Chung et al11 suggested in a recent study that
statins may increase femur mineral density in men with type 2 diabetes mellitus.
It currently is not known whether the observed effects on bone density
have clinical relevance in preventing bone fractures in patients treated with
statins. If this is the case, elderly patients with hyperlipidemia who are
also at increased risk of developing osteoporosis (particularly postmenopausal
women) potentially may have an additional benefit from therapy with statins.
We conducted a large nested case-control analysis using the UK-based
General Practice Research Database (GPRD) to determine whether use of statins,
fibrates, or other lipid-lowering drugs is associated with a reduced risk
of bone fractures.
Data were derived from the GPRD, which has been described in detail
Since 1987, more than 3 million residents in the United Kingdom have been
enrolled with selected general practitioners who have agreed to provide data
for research purposes to the GPRD. The age and sex distribution of the patients
enrolled is representative of the entire UK population. The general practitioners
received 12 months of instruction on standardized recording via computer of
anonymous information, which they agreed to supply continuously to academic
researchers. The information recorded includes patient demographics and characteristics
(eg, height, weight, and smoking status); symptoms; medical diagnoses; referrals
to consultants; hospital admissions; and drug prescriptions, including the
specific preparation, route of administration, dose, and number of tablets
for each prescription. On request, hospital discharge and referral letters
are available for review to validate the diagnoses recorded in the computer
record. The GPRD currently encompasses some 30 million person-years of follow-up;
it has been the source for numerous epidemiological studies in recent years,
and the accuracy and completeness of these data have been well documented
We analyzed data from the GPRD starting in the late 1980s through September
Within the GPRD, a base population consisting of 3 separate groups was
identified: group 1 included all patients who received at least 1 prescription
for a statin (ie, atorvastatin, cerivastatin, fluvastatin, pravastatin, or
simvastatin), a fibrate (ie, bezafibrate, ciprofibrate, clofibrate, fenofibrate,
or gemfibrozil), or a lipid-lowering drug other than statins or fibrates (ie,
colestipol hydrochloride, cholestyramine, acipimox, or nicotinic acid) at
age 50 through 89 years (at the time of the first prescription). Group 2 comprised
patients with a computer-recorded diagnosis of hyperlipidemia (International Classification of Diseases, Eighth Revision [ICD-8], code 272.x) who did not receive any lipid-lowering drug treatment.
Group 3 was a random sample of 50,000 patients who had neither a computer-recorded
diagnosis of hyperlipoproteinemia nor a prescription for a lipid-lowering
drug at any time. Within a base population consisting of these 3 groups, we
followed each patient from the start of follow-up until the person developed
a fracture, left the practice, or died. We defined start of follow-up as the
date of the first prescription for any lipid-lowering study drug as defined
above (group 1) or as the date exactly 1 year after computer recording of
prescriptions began (groups 2 and 3). All patients were aged 50 through 89
We excluded individuals with a computer-recorded diagnosis of osteoporosis,
osteomalacia, cancer (excluding nonmelanoma skin cancer), or alcoholism and
patients who used bisphosphonates (considered an indicator for osteoporosis
or bone metastases) prior to start of follow-up.
Within the base population (ie, the 3 groups combined) we identified
by ICD-8 codes all patients who developed a first-time
diagnosis of a fracture of the femur; humerus; hand, wrist, or lower arm;
vertebrae; clavicle; foot or malleolus; or an unspecified fracture after start
of follow-up. The date of the fracture will subsequently be referred to as
the index date. We reviewed a random sample of 200
case records by hand to verify the computer-recorded diagnosis and quantify
the proportion of patients with fractures due to severe trauma (eg, vehicular
collision). Within this sample, there was only 1 case patient with evidence
for fracture due to severe trauma, a proportion that we considered negligible,
so we included all cases of fracture identified on computer.
From the base population, we randomly selected up to 6 control patients
per case patient matched for age (±5 years), sex, general practice
attended, calendar time (by using the same index date as for cases; ie, the
date of the first diagnosis of a bone fracture), and years of prior history
in the GPRD (matching on the year of start of follow-up [±1 year]).
Furthermore, controls had to be alive and still enrolled at the index date.
The same exclusion criteria were applied to control patients as to case patients.
We conducted a matched analysis (conditional logistic regression) to
explore the association between the risk of having a bone fracture and type
of exposure (statins, fibrates, other lipid-lowering drugs, mixed use [switched
between drug classes or used 2 or more drug classes concomitantly, regardless
of timing of exposure] or none), exposure timing (current use, defined as
having had the last prescription for a lipid-lowering drug <30 days preceding
the index date; recent use, within 30-89 days; and past use, ≥90 days prior
to the index date), and exposure duration (by number of prescriptions, in
categories of 1-4, 5-9, 10-19, and ≥20 prescriptions). A prescription for
a lipid-lowering drug usually lasts for 30 days.
In addition to matching for age, sex, general practice, calendar time,
and years of history recorded in the GPRD prior to the index date, we controlled
the analysis for the potential confounders smoking status (none, current,
past, or unknown), body mass index (<25, 25-29.9, ≥30 kg/m2,
and unknown), exposure to oral or inhaled corticosteroids, hormone replacement
therapy with estrogens, and number of general practice visits prior to the
The analysis was performed using SAS, version 6.12 (SAS Institute Inc,
Cary, NC). Odds ratios (ORs) are presented with 95% confidence intervals (CIs); P values are 2-tailed.
The base population comprised 91,611 individuals, consisting of 28,340
users of lipid-lowering drugs (group 1), 13,271 individuals with a diagnosis
of hyperlipidemia who did not use lipid-lowering drugs (group 2), and 50,000
randomly selected individuals (group 3). During follow-up, 3940 individuals
developed a bone fracture and were defined as cases: 705 in group 1 (2.5%),
681 in group 2 (5.1%), and 2554 in group 3 (5.1%). A total of 23,379 control
patients were matched to the 3940 case patients, averaging 5.93 controls per
case. For 7 cases (0.18%), no eligible control could be identified; more than
99.4% of cases had 6 matched controls. The average number of years of medical
history recorded prior to the index date was similar for cases (3.3 years)
and controls (3.2 years). The distributions of age and sex and the independent
associations between patient characteristics (body mass index, smoking status,
use of corticosteroids or estrogens, and number of general practice visits
before the index date) and the risk of having a bone fracture (as assessed
in univariate analyses) are displayed in Table 1. These covariates have been taken into account in all subsequent
When we compared cases with a diagnosis of hyperlipidemia who did not
use lipid-lowering drugs with cases without a diagnosis of hyperlipidemia,
the risk of having a bone fracture was almost identical in the 2 groups. Compared
with the referent of normolipidemic nonusers of lipid-lowering drugs, the
relative risk estimate for hyperlipidemic nonusers of lipid-lowering drugs
was 0.95 (95% CI, 0.86-1.05). Since there was no material difference between
normolipidemic and hyperlipidemic nonusers of lipid-lowering drugs, we combined
all nonusers into 1 reference group for subsequent analyses.
Compared with this reference group of nonusers of any lipid-lowering
drugs, the ORs for current exposure of 1 to 4, 5 to 19, or 20 or more computer-recorded
prescriptions for statins prior to the index date were 0.51 (95% CI, 0.33-0.81),
0.62 (95% CI, 0.45-0.85), and 0.52 (95% CI, 0.36-0.76), respectively, after
adjusting for body mass index, smoking status, number of general practice
visits, and use of corticosteroids or estrogens. The adjusted ORs for any
current, recent, or past exposure to statins, regardless of the total number
of prescriptions, were 0.55 (95% CI, 0.44-0.69), 0.67 (95% CI, 0.50-0.92),
and 0.87 (95% CI, 0.65-1.18), respectively (Table 2).
As compared with the same reference group of nonusers of any lipid-lowering
drugs, current, recent, or past exposure to fibrates (regardless of the number
of prescriptions) yielded adjusted ORs of 0.87 (95% CI, 0.70-1.08), 1.05 (95%
CI, 0.79-1.41), and 0.85 (95% CI, 0.64-1.13), respectively. Current, recent,
or past use of other lipid-lowering agents resulted in adjusted ORs of 0.76
(95% CI, 0.41-1.39), 1.19 (95% CI, 0.66-2.14), and 0.97 (95% CI, 0.71-1.34),
respectively (Table 2).
We further stratified the analysis of current use of statins or fibrates
by age (50-69 and 70-89 years), sex, and outcome (fracture of femur, humerus
or arm, vertebrae, malleolus or foot, or other [including clavicle and unspecified
fractures]) to detect possible effect modification. The results of these subanalyses
did not suggest that the effects of statins on fracture risk differed materially
by bones affected, age groups, or sex. Odds of fracture among those with current
exposure to fibrates differed between men (OR, 0.50; 95% CI, 0.30-0.83) and
women (OR, 1.01; 95% CI, 0.79-1.28) (Table
3). We also explored the effect of current exposure to individual
lipid-lowering drugs on the risk of developing bone fractures. The effects
were consistent within groups of lipid-lowering drugs; ie, all individual
statins were associated with decreased fracture risks.
From the patient records, we assessed additional covariates that have
been related to an altered risk of having a bone fracture and explored whether
their inclusion in the multivariate regression model changed the results.
There was no evidence of confounding of the association between lipid-lowering
drugs and the bone fracture risk by including dichotomous variables for a
history of chronic renal failure, hyperthyroidism, hyperparathyroidism, inflammatory
bowel disease, malnutrition or malabsorption, or current exposure to benzodiazepines,
neuroleptics, antidepressants, antihypertensives, calcium, fluoride, or vitamin
D preparations, although current exposure to drugs affecting the central nervous
system (ie, benzodiazepines, antidepressants, and antipsychotics) was associated
with a slightly increased risk of bone fractures (OR, 1.20; 95% CI, 1.08-1.34).
The findings of this large nested case-control analysis indicate that
exposure to statins (HMG-CoA reductase inhibitors) is associated with a substantially
lower risk of developing fractures in humans. The association was mainly present
for current users of statins (OR, 0.55; 95% CI, 0.44-0.69) and could be identified
even after relatively short exposure duration (ie, 1-4 prescriptions, corresponding
to a treatment duration of approximately 1-4 months). The reduced fracture
risk was observed in various skeletal sites. There was no evidence for material
effect modification by age or sex in this study population because the association
between statin exposure and fracture risk did not differ by age group or sex.
In contrast, there was little evidence that fibrates or other lipid-lowering
drugs are related to altered bone fracture risk, even though the current analysis
does not entirely rule out an effect of fibrates on fracture risk. Current
fibrate use was associated with a reduced odds of fracture in men and of vertebral
fractures. However, some of these findings were based on small numbers, and
the findings overall suggest that the association between drug use and decreased
fracture risk may be most pronounced for statins.
Exposure to statins was associated with a decreased fracture risk even
after a short exposure duration of a few weeks to a few months. Mundy et al7 reported an increase in bone formation and some inhibition
of osteoclastic activity by statins in their rodent model after 5 weeks of
treatment. Other studies have shown that intervention with bisphosphonates
reduces osteoclastic bone resorption significantly after 1 week of treatment.17,18 Thus, a rapid change in bone remodeling
seems possible, but the dynamics of the effect of statins on bone remodeling
needs further investigation.
As in previous investigations, we also found independent effects of
several covariates on the fracture risk, such as a small decreased risk of
osteoporotic fractures in relation to increasing body mass index, substantially
decreased fracture risk associated with estrogen use, and increased fracture
risk for longer-term use of oral corticosteroids and drugs and affecting the
central nervous system (ie, benzodiazepines, antidepressants, and antipsychotics)
in the current study population.
As with all observational studies, biases or unknown confounders cannot
be completely ruled out as alternative explanations for the findings. A limitation
of this study is the lack of information on physical activity of cases and
controls. However, the proposition that individuals may dramatically change
their lifestyle habits and begin exercising after a diagnosis of hyperlipidemia
cannot sufficiently explain the findings because physical activity has only
a moderate effect in slowing age-related bone loss, and its effect in reducing
the fracture risk can only be expected in the long-term.19,20
In addition, it seems unlikely that such substantial confounding would selectively
affect statins but not other classes of lipid-lowering drugs. The same is
true for a possible confounding effect of low socioeconomic status, which
may be related to both decreased access to medical care and to the likelihood
of getting treatment with lipid-lowering drugs. We attempted to control for
this possibility at least in part by matching for general practice. Regardless,
it seems unlikely that potential confounding by this parameter would selectively
affect the findings for statins but not for fibrates or other lipid-lowering
drugs. In addition, subtle differences in access to medical care do not seem
to be particularly relevant for an acute outcome that requires medical attention
regardless of socioeconomic status, such as bone fracture. An exception may
be vertebral fractures because a considerable number of vertebral fractures
remain undiagnosed; it has been reported that less than one third of patients
with vertebral deformities present to medical practitioners.21
The number of vertebral fractures was quite low in the current study; however,
possible underdiagnosis of this type of fracture does not affect the validity
of the diagnosed and computer-recorded fractures in general.
In epidemiological research, it is generally important to include only
well-validated cases in an analysis. For this particular study, we did not
validate the case diagnoses (ie, fractures) by review of original medical
records because this outcome of interest has been well documented in the computer
records and left little room for misclassification.
In conclusion, we found that current use of statins in men and women
aged 50 years or older was associated with a reduced risk of fracture. This
association was much weaker or not present for fibrates and other lipid-lowering
drugs, and there was no risk difference between nonusers of lipid-lowering
drugs with or without a recorded diagnosis of hyperlipidemia. Despite strong
evidence from the current analysis, it is necessary to obtain additional information
from controlled trials to further investigate a possible causal effect of
statins on bone fracture risk, and, if an effect exists, further assess the
timing of onset of such an effect.