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Author Affiliations: Departments of Medicine, and Epidemiology and Biostatistics, University of California, San Francisco.
Two articles in this issue of THE JOURNAL1,2
report that 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors
(statins) that reduce blood cholesterol levels and the risk of cardiovascular
disease3 also might substantially reduce the
risk of fractures. The studies are impressively large and well done, and some
clinicians might be tempted to prescribe statins in the hope of preventing
or treating osteoporosis. However, these are observational studies, not randomized
trials, and they do not provide enough certainty for clinicians to begin prescribing
statins to reduce fracture risk.
The bone-forming potential of statins was uncovered by Mundy and colleagues4 in the course of screening thousands of chemicals
for the ability to increase the synthesis of bone morphogenic protein 2, a
growth factor that causes osteoblasts to proliferate, mature, and form new
bone. Mundy et al4 then showed that 5 days
of lovastatin or simvastatin injections into the subcutaneous tissue over
the surface of the skulls of mice caused formation of cortical bone, and oral
administration of statins in intact or ovariectomized rats increased trabecular
bone volume by 90%.
Several clinical trials have shown that bisphosphonates, such as alendronate
sodium and risedronate sodium, decrease bone resorption, and, in women with
osteoporosis, substantially reduce fracture risk.5-7
It is fascinating to note that both statins and the nitrogen-containing bisphosphonates
(alendronate and risedronate) work by inhibiting different steps in the pathways
that branch from the synthesis of cholesterol from acetyl CoA.8
Statins block an early step, the conversion of HMG CoA to mevalonate (Figure 1); supplying mevalonate, the first
downstream metabolite, prevents the effect of statins on bone.4
However, the mechanism of the effect of statins on bone remains to be elucidated.
In contrast, nitrogen-containing bisphosphonates (alendronate and risedronate)
block the formation of geranylgeranyl pyrophosphate and farnesyl pyrophosphate.8 This, in turn, inhibits the prenylation of small glutamyl
transpeptidases, such as Ras, Rho, Rac, and Rab. Prenylation adds a lipid
chain that anchors these glutamyl transpeptidases into the membrane of the
osteoclast, a step that is required for osteoclasts to form ruffled borders
that seal off a section of bone, and allow release vesicles of proteolytic
enzymes and acid that physicochemically dissolve bone underneath the cell.
By blocking this pathway, nitrogen-containing bisphosphonates also trigger
apoptosis of osteoclasts.8,9 Whether
statins exert similar effects on osteoclasts remains to be studied. Estrogen
decreases low-density lipoprotein (LDL) cholesterol and bone resorption.10,11 It is not yet known whether estrogens
might also act, in part, by affecting steps in the mevalonate pathway.
Although statins and bisphosphonates both act in the same general pathway,
they may have different effects on bone. Bisphosphonates reduce bone resorption
and do not significantly stimulate bone formation.8
Conversely, statins predominantly seem to increase bone formation; the effect
of statins on bone resorption is not known, although Mundy et al4
noted that simvastatin decreased the number of osteoclasts by about 25% in
Statins have been tested in clinical trials and used widely for more
than a decade.12 This recent discovery that
statins can have profound effects on bones is a reminder that drugs that influence
fundamental cellular processes often are developed for one system or condition
and are later found to have major, unanticipated effects on other systems
and diseases. Indeed, statins may have other effects that are not yet appreciated.
For example, based on data from the Heart and Estrogen/progestin Replacement
Study (HERS), Grady et al13 recently reported
that women taking statins had a 50% lower risk of venous thrombosis than nonusers.
The recurring story of the discovery of surprising new effects of drugs after
they have been approved for use indicates that the current processes of testing
drugs imperfectly predicts the various clinical effects of their long-term
use in clinical practice.
The case-control studies by Meier et al2
and Wang et al1 paint a consistent picture:
women and men who were taking any of a variety of statins had a lower risk
of fractures than those who were not taking statins. The reductions were large
and statistically significant: Meier et al report a 45% lower risk of all
types of fractures and 88% lower risk of hip fractures, whereas Wang et al
report a 43% to 50% lower risk of hip fractures in users vs nonusers of statins.
Adjustment for a variety of potential confounding factors did not influence
the results. Obesity is a particularly important confounder because it is
associated with higher levels of LDL cholesterol and lower risk of hip fracture.
Although data on weight were not available in the database used by Wang et
al, adjustment for body mass index did not affect the relationship between
statins and risk of fracture reported by Meier et al. It is possible that
patients with higher LDL cholesterol or who receive or adhere to treatment
with drugs to reduce cholesterol have a lower risk of fractures. However,
both studies show that use of nonstatin cholesterol–lowering drugs was
not associated with a reduction in risk of fractures. These results are also
consistent with preliminary findings from 2 other observational studies showing
that women who take statins, but not those taking other cholesterol-lowering
drugs, have a lower risk of hip fractures.14
Other large observational studies are analyzing the association between statin
use and risk of fracture; since positive results tend to be published before
negative ones, other, conflicting reports are likely to appear.
Wang and colleagues found that the risk of hip fractures decreased with
increasing statin use during the previous 3 years, as might be expected if
statins cause a progressive increase in bone mass with continuous use. In
contrast, Meier and colleagues observed a 49% decrease in risk of hip fracture
among those who had received 1 to 4 months' worth of prescriptions of statins
and no further reduction with longer use. Although bone formation is accelerated
within several weeks of statin administration in rodents,4
it is more difficult to imagine that just 1 to 4 months of oral use of current
statins could increase bone mass and improve bone architecture enough to halve
the risk of hip fracture. This result raises the possibility that, despite
the extensive adjustments for potential confounders, patients taking statins
started with a lower risk of fractures due to confounding characteristics
rather than to effects of the drug. This can only be clarified by a large
Neither study included measurements of bone mass. A retrospective study
of patients with diabetes mellitus suggested that statin use was associated
with somewhat reduced bone loss in men but not women.15
Bauer et al14 found that statin users appeared
to have slightly higher bone mass than those not taking statins. The associations
between statin use and 2% to 4% higher bone density in these studies does
not seem large enough to account for the large decrease in risk of fracture
reported by Meier et al and Wang et al. Statins may add bone to the periosteal
surface of bone, increasing their width, and, because wider bones are stronger
than narrow ones, statins could increase the strength of bones somewhat more
than expected from improvements in bone density. However, randomized trials
showing that statins increase bone mass in humans would bolster the proposition
that these agents reduce the risk of fractures.
Statins that are currently approved for lowering cholesterol and reducing
the risk of cardiovascular disease may not be the most effective drugs for
increasing bone mass. These agents preferentially affect HMG-CoA reductase
in the liver, not bone, and they have been selected and developed for their
effects on circulating cholesterol concentrations. For example, Mundy and
colleagues found that 1 hydrophilic statin, pravastatin sodium, did not increase
bone formation in bone organ cultures (Gregory R. Mundy, MD, written communication,
May 2000). The best dose and mode of administration of statins to improve
bone mass in humans are not known. Mundy et al4
found a progressive increase in bone mass after short-term exposure to statins.
Perhaps intermittent use of high doses will stimulate bone formation more
effectively than daily use of standard doses. It is possible that statins
will reach bone more effectively if they are delivered by transdermal patch
to bypass the liver. Research is needed to find formulations, doses, and routes
and schedules of administration that optimize the effects of statins on bone
without diminishing their cardiovascular benefits.
It is particularly important to demonstrate the effectiveness and safety
of drugs that may be widely used by asymptomatic people to prevent disease.
Even though statins seem to be quite safe,12
it is important to remember that drugs that seem effective in observational
studies may not prove to be effective in randomized trials. For instance,
sodium fluoride increases bone mass, and observational studies initially demonstrated
a substantial reduction in risk of vertebral fracture.16
However, a randomized trial showed that daily administration of 75 mg of sodium
fluoride increased spine bone density but failed to reduce the risk of vertebral
fractures and even increased the risk of peripheral fractures.17
Fluoride can stimulate formation of abnormal bone; very early observations
suggest that the new bone stimulated by statins appears normal (Gregory R.
Mundy, MD, written communication, May 2000).
Recent studies of estrogen therapy reinforce the point that the results
of observational studies of drugs sometimes produce different results than
randomized trials. Excellent observational studies concluded that estrogen
therapy reduced the risk of coronary heart disease, thus leading many to promote
estrogen for prevention of heart disease, especially among women with coronary
disease.18 However, results of the HERS trial
showed that 4 years of treatment with estrogen and medroxyprogesterone did
not decrease the risk of coronary heart disease events among postmenopausal
women with established coronary disease and raised the sobering possibility
that estrogen might even transiently increase the risk of death from heart
disease.11 It is important to keep these lessons
in mind when considering the impressive results of observational studies about
statins and risk of fractures.
Thus, recommendations about prescription of statins to prevent fractures
must await the results of rigorous randomized trials that are large enough
to determine whether currently approved or new statins improve bone mass and
reduce the risk of fractures. In the meantime, patients with osteoporosis
should be treated with agents that have been proven to reduce the risk of
Cardiovascular disease is the most common cause of death among women with
osteoporosis.20 Therefore, even among women
with osteoporosis, physicians should continue to prescribe statins according
to guidelines for improving cholesterol metabolism and reducing the risk of
cardiovascular disease.21,22 We
eagerly look forward to finding, proving, and defining a way of using statins
that might maximize reduction in death and disability from both cardiovascular
disease and fractures.
Cummings SR, Bauer DC. Do Statins Prevent Both Cardiovascular Disease and Fracture? JAMA. 2000;283(24):3255–3257. doi:10.1001/jama.283.24.3255
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