Increased Bone Density

Table 2: Studies that Suggested an Increased Bone Density Associated with Statins
Studies that found a significantly lower risk

*In patients with type 2 diabetes mellitus
†In postmenopausal women
‡Comparing fluvastatin vs pravastatin in postmenopausal women

Diabetes may itself affect bone metabolism. The bone density of patients with type 1 diabetes is lower than in healthy subjects; in contrast, hyperinsulinemia and the relatively high body mass index in patients with type 2 diabetes seem to protect against bone loss.

Bauer et al,(18) in their analysis of data from the SOF and FIT studies, found that women taking statins but not other lipid-lowering drugs had higher bone densities of the hip; however, this association did not reach statistical significance.

Edwards et al,(24) in the United Kingdom, measured the bone density of the hip and spine in 41 postmenopausal women taking statins and in 100 matched controls. The median length of statin use was 48 months; 51% of the statin users took simvastatin, 24% took pravastatin, 15% took atorvastatin, and 10% took fluvastatin.

Bone mineral density was significantly higher in statin users, and the difference remained significant after adjustment for age, height, and weight. In contrast, in another 46 women with total cholesterol levels higher than 290 mg/dL at baseline who did not receive statins, bone density did not differ at the spine or hip compared with controls.

Watanabe et al,(25) performed a small randomized trial comparing the effects of fluvastatin and pravastatin in postmenopausal women. At 1 year, neither drug had any effect on the bone mineral density of the whole body, but the bone mineral density of the lumbar spine had increased by 1% in the fluvastatin group, compared with a 2% decrease in the pravastatin group.

Why Were the Findings Inconsistent?

Possible reasons for the divergent findings in the studies of fracture risk include the following:

The effect of statins on bone may be relatively weak, apparent in some studies but not in others.

Statins may have been given preferentially to patients who were less frail or otherwise at lower risk of fracture. (As with all observational studies, biases or confounders such as this cannot be entirely excluded.)

The control groups were small. In most of these studies, the control group of hyperlipidemic patients using non-statin agents was smaller and thus less robust as a comparative group.

Obesity was not controlled for. Low body mass is a risk factor for osteoporotic fractures, and high body mass is associated with high blood cholesterol concentrations. Therefore, patients treated with cholesterollowering drugs may have a lower intrinsic risk of fracture because of the protective effect of increased adipose tissue. Future studies should include calculations of the body mass index, because obesity may be an important underlying factor that leads to both statin use and a reduced risk of hip fracture.

The physical activity of subjects was not quantified, even though physical activity is associated with lower fracture risk.

Doses may have been too low. Higher doses of statins may be needed to affect bone than to lower cholesterol. Current statins target the liver, where most cholesterol synthesis occurs, rather than the bones, and less than 5% of a given dose reaches the systemic circulation.(26) Indeed, the efficacy and safety of statins in treating hyperlipidemia is due mainly to their selective localization to the liver. Mundy et al,(13) in their studies in rats, used doses about 10 times higher than those typically given to patients.

Duration may have been too short.With their limited bioavailability for osteoclasts, statins may need to be taken long-term to produce a significant biologic response.

Future Study Requirements

Prospective randomized controlled trials are needed to better exclude the possibility of unmeasured confounding variables and to delineate precisely the role of statins in skeletal health.

Although the consensus seems to be that statins increase bone density, not all studies demonstrated this association. Furthermore, the primary end points measured in many of these studies did not include bone density or fracture rates. Retrospective analysis of data may be misleading, because not all events and outcomes were comprehensively recorded.(27)

It also is interesting that pravastatin has recently been shown to be ineffective in increasing bone morphogenetic protein-2 or stimulating bone formation, perhaps because of its molecular charge.(28) As might be predicted, the largest clinical trial using pravastatin(21) failed to demonstrate fracture protection. Excluding this pravastatin trial from the analysis may increase the association between statins and decreased risk of fracture.

Cruz AC, Gruber BL. Statins and Osteoporosis: Can these Lipid-Lowering Drugs also Bolster Bones? Cleve Clin J Med 2002;69:277-278.