Improvement of Bone Healing by Combined Treatment with Selective Androgen and Estrogen Receptor Modulators in Female and Male Rats

Vollständiger Abstract

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Abstract With age, both men and women experience a decline of sex-hormones and impaired bone repair. This study examined whether bone healing could be improved by combined treatment with the selective androgen and estrogen receptor modulators ostarine (Ost) and raloxifene (Ral), and compared its efficacy with monotherapy in female and male rat models. Three‑month‑old female (Experiment 1, n = 15/group) and 8‑month‑old male (Experiment 2, n = 15/group) Sprague–Dawley rats were either intact (healthy control) or ovariectomized/orchiectomized (Ovx/Orx). Ovx/Orx rats received daily either no treatment, Ost, Ral, or combined Ost + Ral at the respective monotherapy doses. Eight weeks after Ovx or 12 weeks after Orx, rats underwent bilateral metaphyseal osteotomy of the tibia with plate fixation. Healing was assessed five in females or 6 weeks in males later by micro‑CT, biomechanics, and histology. Increased total, callus, and cortical densities as well as bone volume fraction were observed in the Ost + Ral group, accompanied by reduced callus volume and surface area, indicating advanced healing. The effect of Ost + Ral was stronger than that of Ral, whereas Ost alone did not alter bone parameters. Biomechanical properties were improved in the Ral and Ost + Ral groups relative to Ovx/Orx controls. Uterus weight was lowest in Ovx and Ovx + Ral groups and enhanced by Ost and Ost + Ral. Prostate weight was lowest in Orx and Orx + Ral rats and increased by Ost. The combination with Ral reduced the androgenic effect of Ost on prostate. Combined treatment may represent a promising approach for osteoporotic bone repair in both sexes, though potential side effects of Ost require consideration.