Simvastatin therapy in higher dosages deteriorates bone quality: Consistent evidence from population-wide patient data and interventional mouse studies

Background: Combining mouse experiments with big data analysis of the Austrian population, we investigated the association between high-dose statin treatment and bone quality.Methods: The bone microarchitecture of the femur and vertebral body L4 was measured in male and ovariec-tomized female mice on a high-fat diet containing simvastatin (1.2 g/kg). A sex-specific matched big data analysis of Austrian health insurance claims using multiple logistic regression models was conducted (simva-statin 60-80 mg/day vs. controls; males: n = 138,666; females: n = 155,055). Results: High-dose simvastatin impaired bone quality in male and ovariectomized mice. In the trabecular femur, simvastatin reduced bone volume (mu m3: d, 213 +/- 15 vs. 131 +/- 7, p < 0.0001; 9, 66 +/- 7 vs. 44 +/- 5, p = 0.02) and trabecular number (1/ mm: d, 1.88 +/- 0.09 vs. 1.27 +/- 0.06, p < 0.0001; 9, 0.60 +/- 0.05 vs. 0.43 +/- 0.04, p = 0.01). In the cortical femur, bone volume (mm3: d, 1.44 +/- 0.03 vs. 1.34 +/- 0.03, p = 0.009; 9, 1.33 +/- 0.03 vs. 1.12 +/- 0.03, p = 0.0002) and cortical thickness were impaired (mu m: d, 211 +/- 4 vs. 189 +/- 4, p = 0.0004; 9, 193 +/- 3 vs. 169 +/- 3, p < 0.0001). Similar impairments were found in vertebral body L4. Simvastatin-induced changes in weight or glucose metabolism were excluded as mediators of deteriorations in bone quality. Results from mice were supported by a matched cohort analysis showing an association between high-dose simva-statin and increased risk of osteoporosis in patients (d, OR: 5.91, CI: 3.17-10.99, p < 0.001; 9, OR: 4.16, CI: 2.92-5.92, p < 0.001).Conclusion: High-dose simvastatin dramatically reduces bone quality in obese male and ovariectomized female mice, suggesting that direct drug action accounts for the association between high dosage and increased risk of osteoporosis as observed in comparable human cohorts. The underlying pathophysiological mechanisms behind this relationship are presently unknown and require further investigation.