Statin-induced calcific Achilles tendinopathy in rats: comparison of biomechanical and histopathological effects of simvastatin, atorvastatin and rosuvastatin.

PURPOSE: Accumulating clinical evidence indicates the risk of tendinopathy and spontaneous and/or simultaneous tendon ruptures associated with statin use. This experimental study was designed to evaluate and compare the biomechanical and histopathological effects of the three most commonly prescribed statins (simvastatin, atorvastatin and rosuvastatin) on the Achilles tendon in rats. METHODS: Statins were administered by gavage to rats at daily doses of 20 and 40 mg/kg for 3 weeks. One week later, the Achilles tendons were dissected and their biomechanical properties, including ultimate tensile force, yield force and elastic modulus, were determined. The samples were stained with haematoxylin-eosin and examined under a light microscope. The biomechanical properties of the tibia were tested by three-point bending test. Bone mineral density (BMD) and the lengths of tibias were measured by computed tomography. RESULTS: All the statins caused deterioration of the biomechanical parameters of the Achilles tendon. Histopathological analysis demonstrated foci of dystrophic calcification only in the statin-treated groups. However, the number and the total area of calcific deposits were similar between the statin groups. The biomechanical parameters of tibias were improved in all the statin groups. BMD in the statin-treated groups was not significantly different from the control group. CONCLUSION: All the statins tested are associated with calcific tendinopathy risk of which full awareness is required during everyday medical practice. However, statin-associated improvement of bone biomechanical properties is a favourable feature which may add to their beneficial effects in atherosclerotic cardiovascular disease, especially in the elderly.

Fluoroquinolone-induced tendinopathy: etiology and preventive measures.

Tendinopathy is a serious health problem and its etiology is not fully elucidated. Among intrinsic and extrinsic predisposing factors of tendinopathy, the impact of therapeutic agents, especially fluoroquinolone (FQ) group antibiotics, is recently being recognized. FQs are potent bactericidal agents widely used in various infectious diseases, including community acquired pneumonia and bronchitis, chronic osteomyelitis, traveler's diarrhea, typhoid fever, shigellosis, chronic bacterial prostatitis, uncomplicated cervical and urethral gonorrhea and prophylaxis of anthrax. FQs have an acceptable tolerability range. However, many lines of evidence for developing tendinitis and tendon rupture during FQ use have resulted in the addition of a warning in patient information leaflets. FQ-induced tendinopathy presents a challenge for the clinician because healing response is poor due to low metabolic rate in mature tendon tissue and tendinopathy is more likely to develop in patients who are already at high risk, such as elderly, solid organ transplant recipients and concomitant corticosteroid users. FQs become photo-activated under exposure to ultraviolet light, and this process results in formation and accumulation of intracellular reactive oxygen species (ROS). The subsequent FQ-related oxidative stress disturbs mitochondrial functions, leading to apoptosis. ROS overproduction also has direct cytotoxic effects on extracellular matrix components. Understanding the mechanisms of the FQ-associated tendinopathy may enable designing safer therapeutic strategies, hence optimization of clinical response. In this review, we evaluate multi-factorial etiology of the FQ-induced tendinopathy and discuss proposed preventive measures such as antioxidant use and protection from natural sunlight and artificial ultraviolet exposure.

Isotretinoin induced achilles tendinopathy: Histopathological and biomechanical evaluation on rats.

OBJECTIVE: The aim of the present study was to evaluate histopathological and biomechanical effects of isotretinoin on Achilles tendon. MATERIALS & METHODS: Sixteen rats were divided into two groups including the control group (n = 8) and isotretinoin group (n = 8). The control group received 1.42 ml/kg soy oil per day whereas the isotretinoin group received 15 mg/kg/day (gavage dose 1.42 ml/kg) isotretinoin dissolved in soy oil through gavage method for 6 weeks. Achilles tendons were excised at the end of week 6. The tendon samples were evaluated by hematoxylin-eosin under a light microscope. Quantitative evaluation was performed via Movin and Bonar scoring. A computer-monitored tensile testing machine was utilised for biomechanical testing. Biomechanical characteristics of the tendon samples (elastic modulus, yield force, ultimate tensile force) were measured. RESULTS: Histopathological evaluation revealed a significantly higher Movin and Bonar scores in histopathological evaluation. Movin score in isotretinoin group was 4.1 ± 2.5 and it was 2.3 ± 1.0 in control group (p = 0.032). Bonar score in isotretinoin group was 2.9 ± 1.4 and it was 1.6 ± 0.7 in control group (p = 0.022). In line with histopathological evaluation, biomechanical measurements in isotretinoin group (elastic modulus, yield force, ultimate tensile force) were significantly lower than the control group. Elastic modulus in isotretinoin group was 227 ± 27.7 N/mm2 and in control group it was 281.7 ± 38.7 N/mm2 (p = 0.006). In isotretinoin group; yield force was 33.7 ± 4.3 Pa and in control group it was 40.8 ± 5.9 Pa (p = 0.021). Ultimate tensile force in isotretinoin group was 35.7 ± 4.2 Pa and in control group it was 44 ± 7 Pa (p = 0.009). CONCLUSION: The present study detected histopathological and biomechanical negative effect of isotretinoin on Achilles tendon. Therefore, isotretinoin should be questioned in medical history of patients with tendinopathy.

Bilateral asymmetric traumatic hip dislocation with bilateral acetabular fracture: case report.

Bilateral traumatic hip dislocation is a very rare condition. Simultaneous anterior and posterior traumatic dislocation of both hips is even more unusual. A case report of a bilateral asymmetrical hip joint dislocation with bilateral acetabular fracture in a 28-year-old man is presented.

Oral toxicity of pefloxacin, norfloxacin, ofloxacin and ciprofloxacin: comparison of biomechanical and histopathological effects on Achilles tendon in rats.

Four fluoroquinolones (pefloxacin, norfloxacin, ofloxacin and ciprofloxacin) were compared according to their biomechanical and histopathological effects on rat Achilles tendon. Wistar rats were divided into one untreated control and four treatment groups in parallel. Pefloxacin mesylate dihydrate (40 mg/kg), norfloxacin (40 mg/kg), ofloxacin (20 mg/kg) and ciprofloxacin (50 mg/kg) were administered by gavage twice daily for three consecutive weeks. 6 weeks after treatment, the test animals were euthanised and Achilles tendon specimens were collected. A computer monitored tensile testing machine was utilised for biomechanical testing. The mean elastic modulus of the control group was significantly higher than that of the norfloxacin and pefloxacin groups (p<0.05 and p<0.01, respectively). The mean yield force (YF) of the control group was significantly higher than those of ciprofloxacin, norfloxacin and pefloxacin groups (p<0.001, p<0.05 and p<0.01, respectively). The mean ultimate tensile force (UTF) of the control group was significantly higher than of the ciprofloxacin, norfloxacin, and pefloxacin groups (p<0.001, p<0.05 and p<0.01, respectively). Hyaline degeneration and fibre disarrangement were observed in the tendons of the ciprofloxacin, pefloxacin, and ofloxacin treated-groups, whereas myxomatous degeneration was observed only in the ciprofloxacin and pefloxacin groups. In conclusion, these findings in our rat model reveal significant deterioration of biomechanical parameters following fluoroquinolone exposure, and indicate significantly higher biomechanical toxicity for ciprofloxacin and pefloxacin.

Increased osteoblast adhesion on nanoparticulate calcium phosphates with higher Ca/P ratios.

The biological properties of calcium phosphate-derived materials are strongly influenced by changes in Ca/P stoichiometry and grain size, which have not yet been fully elucidated to date. For this reason, the objective of this in vitro study was to understand osteoblast (bone forming cells) adhesion on nanoparticulate calcium phosphates of various Ca/P ratios. A group of calcium phosphates with Ca/P ratios between 0.5 and 2.5 were obtained by adjusting the Ca/P stoichiometry of the initial reactants necessary for calcium phosphate precipitation. For samples with 0.5 and 0.75 Ca/P ratios, tricalcium phosphate (TCP) and Ca(2)P(2)O(7) phases were observed. In contrast, for samples with 1.0 and 1.33 Ca/P ratios, the only stable phase was TCP. For samples with 1.5 Ca/P ratios, the TCP phase was dominant, however, small amounts of the hydroxyapatite (HA) phase started to appear. For samples with 1.6 Ca/P ratios, the HA phase was dominant. Last, for samples with 2.0 and 2.5 Ca/P ratios, the CaO phase started to appear in the HA phase, which was the dominant phase. Moreover, the average nanometer grain size, porosity (%), and the average pore size decreased in general with increasing Ca/P ratios. Most importantly, results demonstrated increased osteoblast adhesion on calcium phosphates with higher Ca/P ratios (up to 2.5). In this manner, this study provided evidence that Ca/P ratios should be maximized (up to 2.5) in nanoparticulate calcium phosphate formulations to increase osteoblast adhesion, a necessary step for subsequent osteoblast functions such as new bone deposition.