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.

Caffeine Uptake into the Vitreous after Peroral Coffee Consumption.

INTRODUCTION: Caffeine and its metabolites have antioxidant activity, scavenging reactive oxygen species. The aim of our study was to measure caffeine concentrations in vitreous samples after peroral caffeine intake. METHODS: This prospective study included patients scheduled for 23-G pars plana vitrectomy with membrane peeling due to epiretinal membranes. The study was performed in two parts: in the first part, patients were recruited into three different groups: group A consisted of habitual coffee drinkers who agreed to drink coffee containing 180 mg caffeine 1 h before surgery (n = 10), group B consisted of habitual coffee drinkers who were not offered coffee before surgery (n = 5), and group C consisted of non-habitual coffee drinkers, forming the control group (n = 5). In the second part (group D) patients (habitual coffee drinkers) agreed to give additional blood serum samples for measurement of caffeine concentration. Harvested samples of vitreous (groups A-D), epiretinal membranes (groups A-C), and blood serum samples (group D) were examined for concentrations of caffeine with gas chromatography-mass spectrometry. RESULTS: Samples of 40 eyes of 40 patients were harvested. The concentrations of caffeine in the vitreous samples were 1,998 ± 967 ng/mL in group A and 1,108 ± 874 ng/mL in group B. In group C, caffeine concentrations were below 176 ng/mL in all vitreous samples. Both groups A and B had significantly higher concentrations of caffeine in the vitreous samples than group C (p < 0.002, p < 0.01, Mann-Whitney U test). Caffeine concentrations in epiretinal membranes were below the limits of detection. Correlation of caffeine concentrations between blood serum samples and vitreous samples in group D was high, with significantly higher caffeine concentrations in the blood serum. CONCLUSION: Coffee consumption leads to significant caffeine levels in the vitreous compared to patients in the control group, and caffeine concentrations in the vitreous showed a high correlation to blood serum concentrations of caffeine after peroral coffee consumption.

Pharmacokinetics of Caffeine in the Lens Capsule/Epithelium After Peroral Intake: A Pilot Randomized Controlled Study.

Purpose: To determine the pharmacokinetics of perorally administered caffeine, a widely consumed and potent dietary antioxidant, in the anterior lens capsule and lens epithelial cells, a crucial cell monolayer for cataract development. Methods: Bilateral cataract patients were scheduled for cataract surgery with a caffeine abstinence of 1 week before surgery of each eye. At the day of surgery of the second eye patients were administered no drink (0-mg group) or coffee with 60-, 120-, or 180-mg caffeine. After capsulorhexis the lens capsule including lens epithelial cells was transferred to a test tube for analysis of caffeine concentration by gas chromatography-mass spectrometry (GC-MS/MS). Results: Coffee consumption significantly (P < 0.05) increased caffeine levels of the lens capsule/epithelium in the 60-, 120-, and 180-mg group. Caffeine concentrations (caffeine ng/lens capsule/epithelium) measured as difference between 1st and 2nd eye were -0.52 ± 1.16 (0-mg group, n = 7), 1.88 ± 2.02 (60-mg group, n = 8), 2.09 ± 0.67 (120-mg group, n = 9), and 3.68 ± 1.86 (180-mg group, n = 9). The increase constant of caffeine in a linear regression model was estimated as a 95% CI 0.02 ± 0.0046 (degrees of freedom; 25; r = 0.85). Conclusions: Peroral intake of coffee significantly increased caffeine concentrations in the lens capsule and lens epithelial cells in a dose-dependent manner. This information is important for further investigations on preventing cataract.

Assessment of Ketamine Binding of the Serotonin Transporter in Humans with Positron Emission Tomography.

Background: Comprehensive description of ketamine's molecular binding profile becomes increasingly pressing as use in real-life patient cohorts widens. Animal studies attribute a significant role in the substance's antidepressant effects to the serotonergic system. The serotonin transporter is a highly relevant target in this context, because it is central to depressive pathophysiology and treatment. This is, to our knowledge, the first study investigating ketamine's serotonin transporter binding in vivo in humans. Methods: Twelve healthy subjects were assessed twice using [11C]DASB positron emission tomography. A total of 0.50 mg/kg bodyweight ketamine was administered once i.v. prior to the second positron emission tomography scan. Ketamine plasma levels were determined during positron emission tomography. Serotonin transporter nondisplaceable binding potential was computed using a reference region model, and occupancy was calculated for 4 serotonin transporter-rich regions (caudate, putamen, thalamus, midbrain) and a whole-brain region of interest. Results: After administration of the routine antidepressant dose, ketamine showed <10% occupancy of the serotonin transporter, which is within the test-retest variability of [11C]DASB. A positive correlation between ketamine plasma levels and occupancy was shown. Conclusions: Measurable occupancy of the serotonin transporter was not detectable after administration of an antidepressant dose of ketamine. This might suggest that ketamine binding of the serotonin transporter is unlikely to be a primary antidepressant mechanism at routine antidepressant doses, as substances that facilitate antidepressant effects via serotonin transporter binding (e.g., selective serotonin reuptake inhibitors) show 70% to 80% occupancy. Administration of high-dose ketamine is widening. Based on the positive relationship we find between ketamine plasma levels and occupancy, there is a need for investigation of ketamine's serotonin transporter binding at higher doses.