Hydroxymethylglutaryl coenzyme A (HMG coA) reductase inhibitors increase new bone formation in vitro and enhance trabecular bone formation in rodents 1. These effects have been attributed to blockade of the mevalonate pathway upstream from the site of bisphosphonate action, which is thought to be mediated by inhibition of farnesyl pyrophosphate and geranylgeranyl pyrophosphate synthesis 23. Currently available treatments for bone loss do not induce new bone formation; consequently, Mundy's observations excited considerable interest in the potential utility of a class of drugs with proven long term safety for a new purpose, treatment of osteopenia or osteoporosis.

The initial analysis in humans of the relationship between HMG coA reductase inhibitors and fractures was carried out on the Study of Osteoporotic Fractures and the Fracture Intervention Trial cohorts. In that report Bauer et al. described a nonsignificant reduction in hip (RR 0.30, 95% CI 0.08,1.18) and non-spine fracture (RR 0.83, 95% CI 0.61, 1.15) associated with current HMG coA reductase inhibitor use 4. A trio of analyses of health-maintenance organization members, New Jersey Medicaid/Pharmacy Assistance/Medicare recipients, and the United Kingdom General Practice Research Database, identified a significantly lower risk of fracture among HMG coA reductase inhibitor users, with odds ratios ranging from 0.48 to 0.55 567. However, subsequent analyses of the UK General Practice Research Database and Women's Health Initiative Observational Study, found no significant reduction in fracture 89 or bone demineralization 10 associated with HMG coA reductase inhibitor use.

A retrospective study of changes in bone mineral density in Korean men and women with type 2 diabetes mellitus revealed higher bone density in HMG coA reductase inhibitor-users compared with non-users after 14 months of follow up 11.

Post-hoc analyses from randomized cholesterol-lowering trials have evaluated effects of HMG coA reductase inhibitors on bone markers and fractures. A 12-week randomized trial in non-osteoporotic individuals found no effect of simvastatin or atorvastatin on C-teleopeptide. Bone-specific alkaline phosphatase was reduced 6% (p < 0.001) among patients assigned to simvastatin, but not atorvastatin 12. A large randomized trial of pravastatin in non-osteoporotic subjects (n = 9014, median age 62 years), identified no reduction in fracture risk 13. However, pravastatin, in contrast to other HMG coA reductase inhibitors, did not induce bone morphogenetic protein-2 formation in vitro14, and consequently might not be expected to affect fracture risk.

This report describes results of a double-blind, placebo-controlled, randomized trial of simvastatin's effects on bone markers in women at high risk for osteoporosis.

Characteristics of the study population are summarized in Table 1. Twenty-four women, ranging in age from 46 to 76 years, were recruited between February and May, 2001. Age, blood pressure, heart rate, body mass index, creatinine and T score were similar in the three treatment groups. Two women in the simvastatin 20 mg group did not complete the study: one developed intolerable drug side effects and one unexpectedly moved abroad. No on-treatment blood samples were available for either of these women. The remaining 22 women are included in analyses of plasma lipids and bone markers. Among these 22 women, adherence to study medication, assessed by pill count, was 94%.

Plasma lipids at baseline and on treatment are summarized in Table 2. After 12 weeks, total cholesterol fell 2%, 25% (p < 0.01 vs. baseline) and 26% (p < 0.01 vs baseline) on placebo, simvastatin 20 mg and 40 mg, respectively. Low density lipoprotein (LDL)-cholesterol was reduced by 7%, 39% (p < 0.01 vs. baseline) and 47% (p < 0.01 vs baseline), respectively. No significant changes from baseline to 12 weeks were observed for triglycerides or high density lipoprotein-cholesterol within treatment groups. When treatment groups were compared, total and LDL-cholesterol were significantly lower at 12 weeks in women randomized to simvastatin 40 mg compared with those assigned to placebo (p < 0.01 for both). LDL-cholesterol was also lower among women in the simvastatin 40 mg group compared with the simvastatin 20 mg group (p < 0.05). All subjects' serum asparate aminotransferase levels remained normal at 12 weeks.

Bone marker concentrations are shown in Table 3. At baseline, levels of bone ALP, NTX-I and CTX-I were similar in the 3 treatment groups. At 6 and 12 weeks, bone marker levels remained similar in the 3 treatment groups. Plasma concentrations of the three bone markers at baseline, 6 and 12 weeks are shown (Fig. 1) for the 8 women assigned to simvastatin 40 mg/day. Neither upward or downward trend is apparent for any of the three bone markers.

This randomized, double-blind, placebo-controlled, dose-ranging trial identified no effect of simvastatin on markers of bone formation or resorption at doses which significantly inhibited HMG coA reductase activity. These results confirm and extend those of Chan et al. who found no effect of simvastatin 20 mg on bone ALP or urine NTX-I 16 in hypercholesterolemic Chinese subjects. Strengths of the current study include the osteopenic cohort, greater ethnic diversity, placebo-controlled design and inclusion of a higher dose of simvastatin as well as the 20 mg dose.

In addition to the possibility that statins actually have neither favorable nor unfavorable impact on bone metabolism in humans, there are several potential alternative explanations for these observations. First, simvastatin may not be the optimal choice of HMG coA reductase inhibitor. Simvastatin was effective both for stimulating bone morphogenetic protein-2 formation in vitro, and inducing bone formation in rodents 1, rendering this possibility less likely. However, the elimination half-life of simvastatin is relatively short 17, and allows for the possibility that agents with longer half-lives, such as atorvastatin 18, might demonstrate efficacy. Second, the dose of simvastatin used may have been inadequate. At the time this trial was designed, simvastatin 40 mg was the highest dose marketed. Subsequently, the 80 mg dose has become available with similar safety profile to the 40 mg dose; the possibility that a higher dose might affect bone turnover cannot be excluded.

Third, the sample size may have been too small to detect changes in plasma concentrations of bone markers. For example, in a 12 week randomized comparison of 2 doses of simvastatin and 2 doses of atorvastatin, with about 200 subjects in each study arm, simvastatin reduced bone ALP by 4.1% and 6.3% from baseline levels at the 40 mg and 80 mg doses, respectively 12. That trial was designed to evaluate lipid effects, not bone markers, so included men and women with unknown bone density status. In interpreting these results, the observed reduction in bone ALP may indicate inhibition of bone resorption, but this was not reflected by a parallel reduction in CTX-I. Further, if new bone was being created, as was observed in the rat model, one might expect bone ALP to rise, as in Paget's disease 19, rather than the observed fall. The change in concentration of a bone marker which reflects a clinically meaningful change, is also an issue. With alendronate, for example, 80% reductions in markers of bone resorption were observed within 6 weeks 20. Thus, a change of a few percentage points may not be clinically important. A comparable reduction in NTX-I to that observed with alendronate would have been readily detected with the sample size studied.

Fourth, the ultrasound entry screen for low bone mineral density may have yielded false-positive results, leading to inclusion of some women with normal bone density. Manufacturer specifications suggest that in 90% of women with Sahara T-score less than -1, osteoporosis will be confirmed by dual x-ray absorptiometry 21. Finally, the duration of treatment may have been insufficient. Alendronate significantly reduces bone marker concentrations within a few weeks 20, but effects of HMG coA reductase inhibitors may not be apparent so quickly.

Our study revealed neither deleterious nor favorable effect of simvastatin on bone turnover during 12 weeks of therapy, and does not support a role for simvastatin as a clinically useful modulator of bone remodeling. Further study is needed to determine whether other agents or regimens may prove more promising.

None declared