Der Einfluss von Raloxifen und Ostarine als Kombinationstherapie aus Östrogen- und Androgenrezeptormodulatoren auf die Knocheneigenschaften bei ovariektomierten Ratten
Osteoporose; Ostarine; Enobosarm; Raloxifen; SARM; SERM
The influence of Raloxifene and Ostarine as a combination therapy of estrogen and androgen receptor modulators on the bone properties of ovariectomised rats
Osteoporosis; Ostarine; Enobosarm; Raloxifene; SARM; SERM
by Marius Adrian Staub
Date of Examination:2024-12-18
Date of issue:2024-12-11
Advisor:PD Dr. Daniel Hoffmann
Referee:PD Dr. Daniel Hoffmann
Referee:Prof. Dr. Stephan von Haehling
Persistent Address:
http://dx.doi.org/10.53846/goediss-10942
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Abstract
English
This study combined two pharmacological classes to investigate their preventive effect on the skeletal system of ovariectomised rats. The osteoanabolic properties of SARM Ostarine and the antiresorptive effect of SERM Raloxifene were examined. They are considered to be a relatively non-toxic alternative to hormone replacement therapy with androgen or oestrogen, with comparable osteoprotective effects. The surgical ovariectomy of three-month-old Sprague Dawley rats results in comparable osteoporotic alterations to those observed in postmenopausal women. A total of 75 animals were subjected to oophorectomy, with 60 of them being divided into four groups. The 15 animals that had not undergone ovariectomy constituted the control group (NON-OVX). The 60 ovariectomised rats were divided into four groups: one group of 15 rats was not subjected to any medication (OVX), while the remaining 45 rats were treated with one of the following three medications: Ostarine (OSTA), Raloxifene (RALO), or a combination of both (OSTA+RALO). The remaining 45 ovariectomised animals were treated with Ostarine (OSTA), Raloxifene (RALO), or a combination of both (OSTA+RALO), with 15 rats in each group. The dosage of the active ingredient Ostarine was 0.4 mg/kg/day, while Raloxifen was administered at a dosage of 8 mg/kg/day. For the combination therapy, the two doses were combined and administered via soya-free feed. Following a 13-week treatment period, the animals were killed, their femora and lumbar vertebrae IV were prepared and their uteri were removed. Additionally, serum samples were collected and analysed for calcium, magnesium, phosphorus, alkaline phosphatase (AP), osteocalcin (OC) and CTX-I levels. The caput femoris and corpus vertebrae were measured using Micro-CT. The mechanical resilience of the bones was evaluated through a biomechanical assessment. Subsequently, the bones were subjected to ashing to determine their organic and inorganic composition, and the femora were examined for their calcium, magnesium, and phosphate content. Monotherapy with Ostarine resulted in an improvement in certain bone characteristics. An increase was observed in the volumetric parameters as determined by Micro-CT, as well as in the maximum force of the femur as measured by the biomechanical test. The analysis of the serum revealed a significant increase in bone resorption (CTX-I) in the OVX group, accompanied by a notable elevation in biomarkers of bone formation and mineralisation (AP and OC). Similarly, the results of the analysis and additional parameters indicated that the moderate osteoanabole effect of Ostarine was insufficient to prevent bone loss resulting from oestrogen deficiency. The monotherapy with Raloxifene resulted in a significant reduction in osteoporotic changes in comparison to the OVX group. The Micro-CT analysis revealed an increase in bone mineral density (BMD) of the vertebrae and the majority of the spongiosa parameters of both bones. The biomechanical test revealed an increase in the maximum force and elasticity of the femur. In the ashing, Raloxifene was observed to maintain the inorganic composition and calcium content of the femur at a higher level in comparison to the OVX group. The serum analysis demonstrateted that the anti-resorptive mechanism counteracted the osteoporotic changes. Additionally, a significant reduction in the consequences of estrogen deficiency on body weight and feed intake was observed in comparison to the OVX group. The combination therapy comprising Ostarine and Raloxifene demonstrated the most pronounced therapeutic efficacy across all outcomes. The combined effect of the SARM and SERM resulted in a significant improvement in both bones when compared to the ovariecto- mised control group. The Micro-CT results demonstrated an increase in bone mineral density (BMD) in the femur and vertebrae, accompanied by a notable improvement in nearly all spongiosa parameters. The biomechanical test revealed an increase in maximum force for both bones, as well as an improvement in the elasticity of the femur. The combination therapy was observed to maintain the inorganic composition of the bone ash. The analysis of the serum revealed clear indications of the synergistic effect of osteoanabolic and antiresorptive actions on turnover. The resorption of bone (CTX-I) was significantly inhibited, while the formation and mineralisation (AP and OC) were increased. It was observed that the minimisation of the negative effects associated with oestrogen deficiency on weight gain and food intake was achieved. Significant increases in uterine weight were observed in the OSTA and OSTA+RALO groups. It would be advisable to examine this relationship in conjunction with the growth of malignant cells, taking into account the stimulation of uterine androgen receptors. This also applies to the serum phosphorus concentration of the Ostarine treated groups in the context of calcifica- tions. Additionally, an increase in the magnesium content of the femora was observed in the OSTA group. These adverse effects suggest that the combination therapy of SARM and SERM is only partially effective in preventing the onset and progression of osteoporotic changes. The combination of osteoanabolic and antiresorptive effects resulted in notable therapeutic outcomes in both bone tissues. However, these outcomes are negated when considering the increased uterus weight observed in the Ostarine-treated groups.
Keywords: Osteoporosis; Enobosarm; Ostarine; Raloxifene; SARM; SERM
