Statins and Osteoporosis: A Clinical Review

Michael J. Gonyeau, Pharm.D.

Disclosures

Pharmacotherapy. 2005;25(2):228-243. 

In This Article

Potential Bone Effects of Statins

Although decreasing bone breakdown is important, rebuilding lost bone would be an added benefit in the prevention of bone fractures. In a study in which more than 300,0000 natural products were evaluated, the researchers discovered that statins may have the potential to build bone.[33] Of the products tested, lovastatin was the only agent to demonstrate an increase in activation of the promoter of bone morpho-genetic protein 2 (BMP-2), a gene that increases osteoblast differentiation and therefore bone formation. The effects of simvastatin, mevastatin, and fluvastatin also were examined, and these agents demonstrated similar results. In organ culture, each statin was added to neonatal murine calvarial (skullcap) bones. All statins demonstrated a 2-3-fold increase in osteoblast differentiation and new bone formation. To examine the effects of statins in vivo, lovastatin and simvastatin were injected 3 times/day for 5 days into the subcutaneous tissue above the murine calvaria. The results of this experiment showed a 50% increase in bone formation. Finally, the investigators tested the effects on bone of statins administered orally. Using female ovariectomized rats as well as female rats with intact ovaries, they found a 39-94% increase in trabecular bone volume after treatment. Overall, the researchers concluded that further investigation was necessary to fully understand the anabolic effects of statins on bone.

The effect of statins on the BMP-2 promoter gene may not be the only mechanism by which these agents can affect bone. Statins exhibit cholesterol-lowering effects by inhibiting HMG-CoA reductase, the rate-limiting enzyme in the cholesterol synthesis pathway (Figure 1).[34] This pathway, however, is responsible for more than just the formation of cholesterol. Compounds important for other cellular functions, including the activation of osteoclasts, also are created through this pathway. Bisphosphonates demonstrate their osteoclastic inhibitory effects at a point downstream to that of statins. They work by inhibiting farnesyl pyrophosphate synthase, an enzyme that inhibits the formation of farnesyl pyrophosphate and geranylgeranyl pyrophosphate, necessary agents for the activation of osteoclasts. Statins, by inhibiting HMG-CoA reductase at a point "upstream" in the pathway, may have similar antiresorptive effects to those of bisphosphonates.[25,28,29,30,31,32,34,35,36,37,38]

A potential link is shown between statins and bones. Adapted from reference 34.

The antiresorptive effects of statins were not demonstrated in an animal study,[39] however. In this study, the effects on BMD, bone formation, and bone resorption of different dosages of simvastatin 1, 5, 10, and 20 mg/kg/day, as well as fixed doses of atorvastatin 2.5 mg and pravastatin 10 mg, were analyzed in female rats. After 12 weeks of administration, rats receiving atorvastatin, pravastatin, and simvastatin 1 mg/kg/day demonstrated a significant decrease in BMD compared with control (atorvastatin 0.094 vs 0.105 g/cm2, p=0.0002; pravastatin 0.096 vs 0.105 g/cm2, p=0.002; simvastatin 1 mg 0.099 vs 0.105 g/cm2, p=0.042). As the dosage of simvastatin increased, the decrease in BMD lessened. When the investigators examined bone formation and resorption, they discovered that the simvastatin 20-mg/kg/day group showed an increase in both parameters compared with controls, with marked increases in osteoid volumes, surfaces, and osteoblast and osteoclast numbers. However, the effects of the lowest dosage of simvastatin exhibited a decrease in bone formation with an increase in bone resorption, resulting in a larger decrease in BMD.

The authors hypothesized that osteoblasts and osteoclasts may be different in their sensitivities to different statins and to different statin dosages. This may explain why lower dosages of simvastatin showed a greater effect on increased bone resorption, whereas higher dosages showed a similar effect on increasing bone formation and bone resorption. Potential reasons for their different results when compared with previously described data[33] include use of alternate statins at different dosages given by different methods of administration. Also, different animal models were used, and the experimental design contrasted between the studies.[33,39]

Although the proposed mechanism of action of the effects of statins on bone seems promising, the results from animal studies are conflicting. There seems to be a missing piece to this puzzle, some other factor involved in the process that has yet to be determined. These studies have demonstrated that statins can have anabolic and antiresorptive effects on bone in vitro and in animal subjects, but clinical trials in humans are needed to understand the clinical significance of these actions.

To answer this question, I conducted a clinical review of statins in the treatment of osteoporosis and their effects on both BMD and fracture rates. Four independent literature searches were performed by using MEDLINE, EMBASE, PreMEDLINE, and the Cochran Database from January 1, 1966-January 7, 2004. Search terms included HMG-CoA reductase inhibitors, statins, osteoporosis, and fracture, in order to identify articles examining any effects of such drugs on osteoporosis, bone remodeling parameters, and various clinical fracture rates. Articles not published in English were excluded.

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