Osteoporosis in murine SLE - Treatment with a tissue-selective estrogen complex

Abstract

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease affecting mainly young women. Almost every organ in the body can be affected and SLE patients often suffer from co-morbidities such as cardiovascular disease and osteoporosis. Postmenopausal women with SLE have a three-fold increase in fractures compared with the healthy population. Treatment with bisphosphonates is associated with side effects and newer anti-osteoporotic treatments need to be tested in SLE patients. MRL/lpr mice spontaneously develop lupus-like symptoms. We show that ovariectomized MRL/lpr mice also develop an osteoporotic bone phenotype and can be used as a model for osteoporosis in postmenopausal SLE. Estrogen has been known to worsen SLE, however there are also contradictory findings available. A tissue-selective estrogen complex (TSEC) comprising estrogen and a selective estrogen receptor modulator (SERM) facilitates the positive effects by estrogen on for example bone, while the negative estrogenic effects on for example the endometrium is blocked by the SERM. The TSEC consisting of conjugated estrogens and the SERM Bazedoxifene (Bza) is approved for treatment of vasomotor symptoms and prevention of postmenopausal osteoporosis. In this thesis we show that treatment with TSEC and Bza protects from trabecular bone loss in ovariectomized MRL/lpr mice, without affecting uterus or lupusassociated disease parameters. B lymphopoiesis and antibody production are regulated by estrogens. We show that TSEC share the estrogenic inhibitory effect on B lymphopoiesis and stimulatory effect on antibody production in healthy mice. These findings have increased the knowledge regarding TSEC as a potential future drug for treating osteoporosis in postmenopausal SLE patients.