The effect of selective androgen and/or estrogen receptor modulators on bone healing in a rat model of aged male osteoporosis

Introduction:

Despite the increasing importance of osteoporosis in elderly men, many questions still remain open. Recently, the application of selective androgen or estrogen receptor modulators (SARMs or SERMs) is gaining interest for the treatment of male osteoporosis and frailty. Ostarine (OS), a SARM has been shown to increase muscle mass in patients with tumor cachexia and improve bone parameters in a rat model of postmenopausal osteoporosis. Raloxifen (RAL), a SERM is an approved treatment for post-menopausal osteoporosis and has been reported to prevent bone loss in osteoporotic males. The present study evaluates the effect of OS and RAL applied alone or in combination on bone healing in a rat model of aged male osteoporosis.

Methods:

8-month old male Sprague-Dawley rats were either left intact (Non-Orx, n = 15) or orchiectomized (Orx, n = 75). Orx rats were divided into 4 groups (n = 15 each): 1) no treatment (Orx), 2) OS treatment (OS), 3) RAL treatment (RAL), 4) OS+RAL treatment (OS+RAL). OS and RAL were administered to the rats along with a soy-free diet for up to 18 weeks. The average daily doses were 0.4 mg/kg body weight (BW) for OS and 7 mg/kg BW for RAL. Twelve weeks after Orx, 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. The weights of body, visceral fat, prostate and levator ani muscle 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+OS and RAL enhanced BV/TV, total and callus BMD, cortical volume and callus biomechanical properties of Orx rats; OS alone did not change bone parameters. Ctx was lower and Alp was higher in OS+RAL compared to Orx. Prostate weight was the lowest in Orx and RAL rats; in Non-Orx it was the highest. OS and OS+RAL at a lesser extend inhibited its atrophy. OS and OS+RAL inhibited the atrophy of levator ani muscle maintaining its weight at the level of Non-Orx rats. BW was lower in RAL and OS+RAL group compared to the others. In OS+RAL group, the visceral fat weight was the lowest among the groups. Food intake was lower in RAL group compared to the others.

Discussion:

RAL and RAL+OS were favorable for bone healing; OS and OS+RAL showed high anabolic activity in muscle. The androgenic effect of OS on prostate was diminished if it was applied in combination with RAL. RAL and RAL+OS both reduced BW. However, the mechanisms were different: RAL decreased food intake; RAL+OS reduced visceral fat weight. Concluding, combination therapy of OS+RAL showed the most favorable effects on the musculoskeletal system in our model of aged male osteoporosis. Its effect on the endocrine system is currently analyzed.