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 ovariectomized 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 (simvastatin 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 (µm3: ♂, 213 ± 15 vs. 131 ± 7, p < 0.0001; ♀, 66 ± 7 vs. 44 ± 5, p = 0.02) and trabecular number (1/mm: ♂, 1.88 ± 0.09 vs. 1.27 ± 0.06, p < 0.0001; ♀, 0.60 ± 0.05 vs. 0.43 ± 0.04, p = 0.01). In the cortical femur, bone volume (mm3: ♂, 1.44 ± 0.03 vs. 1.34 ± 0.03, p = 0.009; ♀, 1.33 ± 0.03 vs. 1.12 ± 0.03, p = 0.0002) and cortical thickness were impaired (µm: ♂, 211 ± 4 vs. 189 ± 4, p = 0.0004; ♀, 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 simvastatin and increased risk of osteoporosis in patients (♂, OR: 5.91, CI: 3.17-10.99, p < 0.001; ♀, 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.

The Fatty Liver Index (FLI) Relates to Diabetes-Specific Parameters and an Adverse Lipid Profile in a Cohort of Nondiabetic, Dyslipidemic Patients.

BACKGROUND: Patients with hyperlipidemia are at high risk for developing a fatty liver. The fatty liver index (FLI) is a noninvasive and well-established method for the estimation of a fatty liver. However, little is known about the metabolic characterization of nondiabetic treated patients with hyperlipidemia who have different risk levels for a fatty liver. METHODS: In this study, 74 nondiabetic patients with hyperlipidemia were divided into 3 groups according to their fatty liver index. A comparison of metabolic characteristics was done. These characteristics included intima media thickness (IMT) and nutritional habits, which were further divided into FLI subgroups with low, intermediate, and high risk for a fatty liver. RESULTS: Patients with hyperlipidemia, with a high risk for a fatty liver (FLI ≥ 60), had subclinical elevations in parameters of carbohydrate metabolism (insulin, fasting plasma glucose, C-peptide) including a higher insulin resistance (quantitative insulin sensitivity check index, QUICKI) compared to lower FLI groups. These patients also presented a higher risk for a metabolic syndrome (p = 0.018), as well as an adverse lipid profile (e.g., high-density lipoprotein [HDL] cholesterol, triglycerides [TG]-HDL ratio). FLI group 3 was characterized by significantly lower levels of omega-3 fatty acids (p = 0.048). CONCLUSION: The fatty liver index relates to diabetes-specific parameters and an adverse lipid profile and is an appropriate index for risk evaluation of metabolic syndrome.