Die Auswirkung vom 5- Lipoxygenaseinhibitor Zileuton auf osteoporotische Wirbelkörper im Rattenmodell

Abstract

According to the World Health Organization, osteoporosis is one of the ten most common diseases in postmenopausal women over the age of 50. In addition to the lack of estrogen in the postmenopause, the influence of the immune system, in particular the interleukin-mediated immune reaction, also plays a decisive role in the development of the disease. One of these important interleukins is 5-lipoxygenase, which activates osteoclast activity. Zileuton is a 5-lipoxygenase inhibitor approved for asthma therapy in the United States since 1997. By inhibiting 5-lipoxygenase, it is assumed that bone resorption is inhibited at the same time, since the stimulation of osteoclast activity is reduced. In this experiment, the influence of zileuton in different doses on vertebral bodies in the ovariectomized rat model of postmenopausal osteoporosis was investigated. The vertebral bodies were chosen for the analyzes because they are most frequently affected by osteoporosis. A total of 69 female, 3-month-old Sprague Dawley rats were observed for a total of 13 weeks and divided into 5 groups. After 1 week of acclimatization, the bilateral ovariectomy was performed to trigger the osteoporosis. 13 animals served as a control group and were not ovariectomized (NON-OVX). Thereafter, 13 animals were placed in the OVX group, 14 OVX animals in the group with 1 mg/kg body weight zileuton, 14 OVX animals in the group with 10 mg/kg body weight zileuton and 15 OVX animals in the group with 100 mg/kg body weight zileuton assigned. 8 weeks after the ovariectomy, Zileuton was administered in the respective concentrations via the soy-free feed for 5 weeks. The vertebral bodies were then removed and cleaned. The 2nd lumbar vertebrae were collected for ashing, the 3rd for compression testing, and the 4th lumbar vertebrae for 2D and 3D CT analysis. In the ashing analysis, the organic and inorganic components as well as phosphate, calcium and magnesium were measured. Significantly higher inorganic fractions were seen in the group with 100 mg/kg bw zileuton compared to the ovariectomized group. There were also significant differences in the inorganic and organic components between the OVX and NON-OVX groups. The organic substance in the OVX group was significantly higher and the inorganic significantly lower than in the NON-OVX control group. The proportions of phosphate, calcium and magnesium did not differ within the groups. The elevated serum levels of alkaline phosphatase in the 10 mg zileuton group indicate a higher rate of bone formation compared to the other groups. When measuring osteocalcin, which is a parameter for bone formation, administration of a high dose of Zileuton (100 mg) showed a positive effect with increased osteocalcin values. Finally, the influence of zileuton on the bone structures was examined by means of a 3D and then a 2D CT analysis. There were differences within the zileuton groups. A higher trabecular density could be measured after the administration of high-dose Zileuton with 100 mg. In addition, the study confirmed the increase in soft tissue volume in all ovariectomized animals compared to the NON-OVX group resulting from the hormone deficiency. Although the administration of 10 mg/kg body weight Zileuton reduced the soft tissue volume significantly compared to the OVX group, the administration of Zileuton cannot clearly improve the bone parameters. The cortical volume fraction and the total bone volume fraction could not be changed by the administration of zileuton (10 and 100 mg/kg body weight) in the OVX rats, while the administration of 1 mg zileuton led to a reduction in the cortical volume compared to the other groups. In summary, it could be shown in this experiment that zileuton as a 5-lipoxygenase inhibitor has a mild effect on the osteoporotic trabecular structures when administered at 100 mg/kg body weight, which together with the increase in inorganic weight and osteocalcin indicate an increased rate of bone formation. Zileuton 10 mg hardly changed bone parameters and only improved soft tissue parameters and alkaline phosphatase. The Zileuton administration of 1 mg/kg body weight is not recommended, as this tends to have a negative effect on osteoporotic bones. Since the effect of Zileuton on osteoporotic bones has proven to be marginal, the usefulness of further research in this regard should be critically questioned.