Effect of selective androgen and/or estrogen receptor modulators on bone in an ovariectomized rat model of postmenopausal osteoporosis

Introduction After menopause, the levels of sex hormones decline, and women often develop postmenopausal osteoporosis. Since steroid hormone therapy has negative side effects, use of non-steroidal selective androgen and estrogen receptor modulators (SARMs or SERMs) could be a possible treatment option. Raloxifene (RAL), a SERM is approved for treatment of postmenopausal osteoporosis. Ostarine (OS), a SARM has been shown to improve bone parameters in ovariectomized rats. The present study analyzes the effect of OS and RAL applied as a combination therapy or alone on bone properties in an ovariectomized rat model of postmenopausal osteoporosis.

Methods Three-month old female Sprague-Dawley rats were either left intact (Non-Ovx, n = 15) or were ovariectomized (Ovx, n = 75). Ovx rats were divided into 4 groups (n = 15 each): 1) no treatment (Ovx), 2) OS treatment (Ovx + OS), 3) RAL treatment (Ovx + RAL), 4) OS + RAL treatment (Ovx + OS + RAL). OS and RAL were administered to the rats along with a soy-free diet for up to 13 weeks. The average daily doses were 0.6 mg/kg body weight (BW) for OS and 11 mg/kg BW for RAL. The lumbar vertebral bodies and femora were examined by micro-CT, biomechanical and ashing analyses. The weights of whole body, visceral fat and uterus were recorded. Serum alkaline phosphatase (Alp) and collagen type 1 cross-linked C-telopeptide (Ctx) were measured. Statistical analysis was performed using one-way ANOVA and Tukey-test (p < 0.05).

Results RAL treatment alone increased cortical and trabecular density, trabecular area and total bone density. OS alone enhanced number of trabecular nodes and trabecular area. Combined OS + RAL treatment improved most of the cortical and trabecular structural parameters and biomechanical properties. In serum, Ctx was lower, and Alp was higher in OS + RAL compared to Ovx. Uterus weight was the lowest in Ovx and Ovx + RAL groups, whereas OS and OS + RAL treatments increased it to the weight in the Non-Ovx group. BW and muscle weight were increased by OS treatment while RAL and RAL + OS maintained them at the level of Non-Ovx rats. Visceral fat weight was reduced after all three treatments.

Discussion RAL and OS possessed distinct effect patterns on the different organ systems. The combination therapy RAL + OS showed stronger effects on bone tissue than single therapies and could be a therapeutic option in the treatment of postmenopausal osteoporosis. However, side effects of OS therapy on the reproductive tissue should be considered.

Keywords selective androgen receptor modulator, selective estrogen receptor modulator, bone, ovariectomized rat model, postmenopausal osteoporosis

Korrespondenzadresse Komrakova Marina, Universitätsmedizin Göttingen, Klinik für Unfallchirurgie, Orthopädie und Plastische Chirurgie, Robert-Koch Str. 40, 37075 Goettngen, Deutschland, Germany

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