Effects of Combined Treatment With Selective Androgen and Estrogen Receptor Modulators Ostarine and Raloxifen on Bone Tissue In Ovariectomized Rats

TL;DR

This study examines how combining two hormone-like drugs affects bone health in rats that had their ovaries removed, showing mixed benefits and safety concerns.

Contribution

The study introduces a novel combination therapy using selective androgen and estrogen receptor modulators for bone protection in ovariectomized rats.

Findings

OST+RAL improved structural and biomechanical bone parameters more than RAL alone.

OST increased bone magnesium and organ weight, but these effects were partially mitigated by RAL.

Combined treatment raised serum phosphorus and luteinizing hormone while lowering magnesium and calcium, raising safety concerns.

Abstract

Hormone replacement therapy in women usually focuses on estrogen and progesterone replacement. But also androgens decrease with age in women. Decrease of estrogen or androgens levels are associated with bone loss, while steroid hormone therapy often leads to negative side effects. A possible solution could be the use of selective receptor modulators (SRMs). Here, a combined treatment with a selective estrogen receptor modulator (raloxifene, RAL) and a selective androgen receptor modulator (ostarine, OST) was investigated in ovariectomized rats. The study was performed using 3-month-old female Sprague–Dawley rats. Fifteen control rats were not ovariectomized (NON-OVX). Sixty rats were ovariectomized and divided into 4 groups (n = 15/group): (1) untreated rats (OVX), (2) rats receiving OST (0.55 ± 0.08 mg/kg body weight [BW]), (3) rats receiving RAL (11.07 ± 1.77 mg/kg BW), (4) rats treated with OST and RAL. The compounds were administered orally as osteoporosis prophylaxis immediately after ovariectomy for up to 13 weeks. Thereafter, the lumbar vertebrae and femora were analyzed.

OST + RAL treatment showed a favorable effect on structural and biomechanical bone parameters, demonstrating some advantages over RAL alone. RAL confirmed its antiresorptive effect on bone tissue without causing negative systemic effects. OST alone was less effective in protecting bone tissue. It increased osteoblast number, serum phosphorus, bone magnesium, and inner organ and uterus weight. The adverse effect of OST on bone magnesium level was attenuated when combined with RAL. Conversely, the combined treatment increased serum phosphorus and luteinizing hormone levels, decreased serum magnesium and calcium, and did not attenuate the organ and uterus weight increase observed after OST, raising safety concerns. These findings highlight the need for cautious evaluation of combination therapies and suggest that there is a need for alternative compounds with improved safety profiles for future osteoporosis treatments.

The online version contains supplementary material available at 10.1007/s00223-025-01431-4.

Figures