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Abstract Purpose  Although androgens are known to protect bone, side effects and poor oral bioavailability have limited their use. We previously reported that S-3-(4-acetylamino-phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-propionamide (S-4) is a potent and tissue-selective androgen receptor modulator (SARM). This study was designed to evaluate the skeletal effects of S-4 in an osteopenic model. Methods  Aged female rats were gonadectomized or sham operated on day 1 and assigned to treatment groups. Dosing was initiated on day 90 and continued daily until day 210. Whole animal bone mineral density (BMD), body weight, and fat mass were determined by dual energy x-ray absorptiometry (DEXA). Regional analysis of excised bones was performed using DEXA or computed tomography. Femur strength was evaluated by 3-point bending. Results  S-4 restored whole body and lumbar vertebrae (L5-L6) BMD to the level of intact controls. Significant increases in cortical bone quality were observed at the femoral midshaft, resulting in increased load bearing capacity. Conclusions  S-4 demonstrated partial/complete recovery of bone parameters to age-matched intact levels. Increased efficacy observed in cortical bone sites is consistent with reported androgen action in bone. The ability of S-4 to promote bone anabolism, prevent bone resorption, and increase skeletal muscle mass/strength positions these drugs as promising new alternatives for the treatment of osteoporosis. [ABSTRACT FROM AUTHOR]

AbstractPurpose??This study was conducted to examine the bone and body composition effects of S-4, an aryl-propionamide derived Selective Androgen Receptor Modulator (SARM) in an ovariectomy induced model of accelerated bone loss.Methods??One hundred twenty female Sprague?Dawley rats aged to twenty-three weeks were randomly assigned to twelve treatment groups. Drug treatment was initiated immediately following ovariectomy and continued for one hundred twenty days. Whole body bone mineral density (BMD), body composition, and lumbar vertebrae BMD were measured by dual energy x-ray absorptiometry. More stringent regional pQCT and biomechanical strength testing was performed on excised femurs.Results??We found that S-4 treatment maintained whole body and trabecular BMD, cortical content, and increased bone strength while decreasing body fat in these animals.Conclusions??The data presented herein show the protective skeletal effects of S-4. Our previous reports have shown the tissue selectivity and muscle anabolic activity of S-4. Together these data suggest that S-4 could reduce the incidence of fracture via two different mechanisms (i.e., via direct effects in bone and reducing the incidence of falls through increased muscle strength). This approach to fracture reduction would be advantageous over current therapies in these patients which are primarily antiresorptive in nature. [ABSTRACT FROM AUTHOR]

Abstract  Testosterone and structurally related anabolic steroids have been used to treat hypogonadism, muscle wasting, osteoporosis, male contraception, cancer cachexia, anemia, and hormone replacement therapy in aging men or age-related frailty; while antiandrogens may be useful for treatment of conditions like acne, alopecia (male-pattern baldness), hirsutism, benign prostatic hyperplasia (BPH) and prostate cancer. However, the undesirable physicochemical and pharmacokinetic properties of steroidal androgen receptor (AR) ligands limited their clinical use. Nonsteroidal AR ligands with improved pharmacological and pharmacokinetic properties have been developed to overcome these problems. This review focuses on the pharmacokinetics, metabolism, and pharmacology of clinically used and emerging nonsteroidal AR ligands, including antagonists, agonists, and selective androgen receptor modulators. [ABSTRACT FROM AUTHOR]