A combination therapy of androgen and estrogen receptor modulators improves bone healing in a rat model of postmenopausal osteoporosis

Introduction Women often develop postmenopausal osteoporosis after the menopause due to the decline in the levels of sex hormones. Recently, we have observed that a combination therapy of non-steroidal selective androgen and estrogen receptor modulators (ostarine and raloxifen) improved bone tissue in osteoporotic rats. The present study evaluates the effect of combination therapy (OS+RAL) on bone healing in an ovariectomized rat model of postmenopausal osteoporosis and compared its effect with the single therapies of OS or RAL

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) Ovx+OS treatment (OS), 3) Ovx+RAL treatment (RAL), 4) Ovx+OS+RAL treatment (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. Eight weeks after Ovx, a bilateral transverse osteotomy of the tibia metaphysis with plate osteosynthesis was performed in all rats. The bone healing was examined by micro-CT, biomechanical and histological analyses. Statistical analysis was performed using one-way ANOVA and Tukey-test (p < 0.05).

Results Total BMD, callus and cortical BMD, bone volume fraction (BV/TV) and cortical volume were higher in RAL and OS+RAL groups than in untreated Ovx group, whereas callus volume and area were lower in these groups. These findings support the advanced bone healing in these treatment groups. Biomechanical properties of the tibia at the osteotomy site were diminished in Ovx rats, whereas OS+RAL and RAL improved it. The effect of OS+RAL was stronger than RAL on bone healing, whereas single OS treatment had no effect on bone parameters studied. Osseous callus bridging occurred earlier in OS+RAL group (17d after osteotomy) than in other groups (Non-Ovx: 21d; Ovx: 20d, Ral: 20d), whereas OS treatment delayed it (25d).

Discussion The combination therapy of OS+RAL showed the most favorable effect on bone healing. RAL treatment improved bone healing to a lesser extent than OS+RAL, whereas OS treatment had no advantage for osteotomized tibia. Considering the positive effect on bone tissue reported previously, the combination therapy of OS+RAL is appeared to be a promising agent in the treatment of postmenopausal osteoporosis and osteoporosis-related fractures. Its effect on the endocrine system is currently analyzed.

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

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

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Publication History

Article published online:
05 March 2021