The Novel Non-steroidal Selective Androgen Receptor Modulator S-101479 Has Additive Effects with Bisphosphonate, Selective Estrogen Receptor Modulator, and Parathyroid Hormone on the Bones of Osteoporotic Female Rats

Abstract

We have studied non-steroidal selective androgen receptor modulators (SARMs) to develop anti-osteoporosis drugs for males and females. Many SARMs have been studied for their anabolic effects on bone or muscle with reduced virilizing effects in male animals. However, the tissue selectivities of these agents in female animals have not been fully evaluated. We evaluated the novel SARM S-101479 from tetrahydroquinoline libraries in ovariectomized (OVX) rats. S-101479 preferentially bound to the androgen receptor with nanomolar affinity among nuclear receptors. It increased the bone mineral density (BMD) of femurs and diminished the effects on the uterus and clitoral gland in OVX rats. We then compared the effect of S-101479 on bone with those of commercial anti-osteoporosis drugs such as alendronate, raloxifene, and teriparatide. Furthermore, we evaluated the effects of combination treatments with these agents in OVX rats. After 16-week treatment, all agents significantly increased BMD, but the magnitude of bone mineral content (BMC) and/or bone size (projected bone area) were different. Alendronate, raloxifene, and teriparatide maintained BMC and bone size in this experimental dose. Only S-101479 increased BMC with bone size on single treatments. In combination treatment, S-101479 significantly increased BMC and bone size compared with single treatments of other agents. S-101479, like natural androgen, may have showed periosteal bone formation of the cortical area and indicated additive effects with commercial anti-osteoporosis drugs. These results indicate that S-101479 may be a useful anti-osteoporosis drug, particularly for patients with established severe osteoporosis.Key words selective androgen receptor modulator; bone anabolic; additive effect Androgens are known to have beneficial anabolic effects on various tissues such as bone, muscle, and red blood cells (RBCs).1-4) However, the clinical use of androgens has been limited because of their undesirable virilizing and metabolic actions. Their effect on the prostate gland is an extremely serious side effect because the risk of prostate cancer or benign prostate hyperplasia may increase. 5,6) The side effects of androgens are not lethal in women, but many virilizing effects (e.g., hirsutism, voice change, and acne) have been observed. 7,8) Anabolic steroids were developed to reduce the side effects of androgens and treat osteoporosis. However, their actions were not sufficient to reduce virilizing effects, and they exhibited hepatotoxic actions. [9][10][11][12] Recently, the actions of non-steroidal selective androgen receptor modulators (SARMs) have been investigated in many laboratories. [13][14][15][16][17] Typically, they were observed to be more tissue-selective than anabolic steroids and were orally available in preclinical models. We have focused on bone anabolic SARMs to develop anti-osteoporosis agents without serious virilizing effects.

Selective Androgen Receptor Modulators (SARMs) Negatively Regulate Triple-Negative Breast Cancer Growth and Epithelial:Mesenchymal Stem Cell Signaling

“…SARMs could evolve as a targeted therapeutic for not only ER-positive breast cancer, but also for aggressive triple negative breast cancers, for which chemotherapy is the only therapeutic option. Additionally, due to their ability to increase muscle mass and restore bone mineral density [23],[25],[43], SARMs will treat muscle wasting and osteoporosis, common side-effects in late-stage breast cancers, while reducing the aggressiveness of breast cancer.…”

Mechanism of the Tissue-Specific Action of the Selective Androgen Receptor Modulator S-101479

“…4B) but 10 mg/kg S-101479 inceased uterine weight in another experiment. 13) Cofactor Profiling Firstly, approximately 180 nuclear …”

“…8,13) S-101479 exhibited bone-anabolic activity similar to the natural androgen 5α-dihydrotestosterone (DHT) and reduced side effects on the uterus and clitoral gland in ovariectomized (OVX) rats. S-101479 exhibited beneficial effects in both single or combination treatments with commercial anti-osteoporosis drugs such as alendronate, raloxifene, and teriparatide.…”

Selective androgen receptor modulators for the treatment of late onset male hypogonadism

“…Likewise, men who are hypogonadal often have low BMD putting them at greater risk for fractures and their associated comorbidities 62. Direct effects of androgens on both cortical and trabecular bone are suggested by knockout animal models and supported by several nonaromatizable, non-estrogenic SARMs demonstrating the ability to maintain bone in preclinical models of osteopenia 63646566. To date the clinical evaluation of SARMs has been of insufficient duration (3 months or less) to characterize effects on relatively slow changing bone parameters.…”