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June 28, 2000

Do Statins Prevent Both Cardiovascular Disease and Fracture?

Author Affiliations

Author Affiliations: Departments of Medicine, and Epidemiology and Biostatistics, University of California, San Francisco.

JAMA. 2000;283(24):3255-3257. doi:10.1001/jama.283.24.3255

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.

Figure. Mevalonate Pathway and Sites of Action of Statins and Nitrogen-Containing Bisphosphonates
Image description not available.
Statins act early in the mevalonate pathway by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase. Nitrogen-containing bisphosphonates interfere with protein prenylation (attachment of a lipid prenyl group to a protein) by inhibiting synthesis of farnesyl pyrophosphate (farnesyl-PP) and geranylgeranyl pyrophosphate (geranylgeranyl-PP). Prenylation is necessary for the proper function of small glutamyl transpeptidases (GTPases), such as Ras, Rho, Rac, and Rab, in the osteoclast. These signaling proteins, when anchored in the osteoclast cell membrane by a lipid prenyl group, regulate osteoclast cell processes, including cytoskeleton organization, vesicle transport, membrane ruffling, and apoptosis.

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 rodents.

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 randomized trial.

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 fractures.5-7,19 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.

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