A tissue-selective estrogen complex as treatment of osteoporosis in experimental lupus

Abstract

Osteoporosis is a common secondary complication in patients with systemic lupus erythematosus (SLE). Current osteoporosis treatment with bisphosphonates has some negative side effects and there is a lack of data regarding newer treatments options for SLE associated osteoporosis. The tissue-selective estrogen complex (TSEC) containing conjugated estrogens and the selective estrogen receptor modulator bazedoxifene (Bza) is approved for treatment of postmenopausal vasomotor symptoms and prevention of osteoporosis. However, it has not been evaluated for treatment of osteoporosis in postmenopausal SLE patients. Ovariectomized MRL/ lpr mice constitute a model for postmenopausal lupus that can be used for osteoporosis studies. We used this model in a set of experiments where the mice were treated with different doses of 17β-estradiol-3-benzoate (E2), Bza, or TSEC (E2 plus Bza), administered in the early or late phases of disease development. The skeleton was analyzed by dual-energy X-ray absorptiometry, peripheral quantitative computed tomography, and high-resolution microcomputed tomography. The lupus disease was assessed by determination of proteinuria, hematuria, and lupus disease markers in serum. Treatment with medium dose TSEC administered in early disease protected ovariectomized MRL/ lpr mice from trabecular bone loss, while there were no differences in lupus disease parameters between treatments. This is the first experimental study to investigate TSEC as a potential new therapy for osteoporosis in postmenopausal SLE.

Bazedoxifene does not share estrogens effects on IgG sialylation

“…However, bazedoxifene displays an estrogen agonistic effect by reducing thymic and gonadal fat weight. In line with previous studies, both in immune-induced and naïve ovariectomized mice [ 9 , 10 , 23 ], we demonstrated that estrogen and bazedoxifene have a stimulatory effect on tibial cortical bone compared with vehicle-treated.…”

“…injected with 17β-estradiol-3-benzoate (E2; 1 μg/mouse/day; Sigma-Aldrich), Bazedoxifene (BZA; 24 μg/mouse/day; Pfizer) dissolved in 100 μl of Miglyol oil or vehicle (100 μl/mice/day; Miglyol oil) 5 times per week for a total of 4 weeks. Treatment doses for E2 and BZA were based on previous findings from our group, which include both healthy ovariectomized C57Bl6 mice [ 11 , 22 ] and in pathogenic conditions such as collagen-induced arthritis a model of RA [ 10 ], and in experimental lupus [ 23 ]. In addition, the body surface is calculated to ensure the dose of BZA used in mice is comparable to doses used in the relevant to human [ 24 ].…”