Abstract P2-13-06: Effect of letrozole on bone and joints in collagen-induced arthritis in mice
Authors: Lintermans A , Verhaeghe J , Van Bree R , Vanderschueren D , Vanderhaegen J , Braem K , Lories R , Neven P 
Published: August 2014

Background Aromatase inhibitors (AIs) are an established treatment modality for postmenopausal hormone-responsive breast cancer. Many of AI-treated patients experience AI-induced musculoskeletal syndrome (AIMSS), which may adversely affect quality of life and treatment adherence. The etiology underlying this syndrome remains unknown. Therefore, a well-established mouse model of human rheumatoid arthritis, collagen-induced arthritis (CIA), was used to evaluate how AIs affect bone and joints in inflammatory joint disease.

Material and methods Thirty-two female DBA/1 mice were divided into 2 groups of 16 mice each; ovariectomy (OVX) or sham operation was performed at 7 weeks of age (=day 0). At day 14, arthritis was induced in all mice by injection of chicken sternal cartilage type II collagen emulsified with an equal volume of Freund's complete adjuvant, followed by a booster injection at day 21. Afterwards, mice were treated with letrozole or vehicle during 30 days. Mice were sacrificed at day 54. Parameters analyzed included clinical CIA score of paws, dual-energy x-ray absorptiometry, microCT of femora, histopathological examination of ankles and paws and IGF-I levels. Analysis was performed with ANOVA, post-hoc tests, general linearized and mixed models.

Results As expected, OVX led to an increased lean and total body weight relative to the sham group. Repeated measurements analysis with mixed models suggested interaction between weight, time and arthritis severity. Serum IGF-I concentrations were significantly higher in the OVX group compared with the sham group, but no differences were observed between letrozole treatment and controls.

Collagen immunization resulted in progressive inflammation of the paws including the ankles that increased up to day 54. Over time, clinical scores for arthritis severity were highest in the OVX/vehicle group. Both letrozole groups had an intermediate course and the lowest scores were seen in the paws of the sham/vehicle group, as expected. Histopathological examination of hematoxylin and eosin-stained sections were in line with these results.

Subcapital BMD at the end of the arthritis experiments was significantly different between the four groups. Post-hoc test confirmed the negative effect of OVX versus sham procedure, in the presence or absence of letrozole treatment. MicroCT analysis showed that OVX induced a significant decrease in bone mineral density and content in both trabecular (volume and number) and cortical bone (volume, area, thickness and medullary area) compared to sham operation in vehicle-treated mice. In the letrozole group, only cortical bone (volume, area inside periost and medullary area) was significantly reduced following OVX. In addition, in the sham group, letrozole induced lower trabecular bone volume and less trabecular numbers compared to vehicle treatment. This was in contrast with the OVX groups; letrozole treatment resulted in significantly better trabecular bone parameters.

Conclusion Not only bone loss but also severity of joint disease was increased by OVX. Remarkably, in contrast to what is observed in humans, letrozole treatment protected the bone and joints after OVX but had negative effects in its absence, thereby providing further evidence for a regulatory effect in joint and bone biology.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-13-06.