Combination treatment with a selective androgen receptor modulator q(SARM) and a bisphosphonate has additive effects in osteopenic female rats.
Recent clinical trials with bisphosphonates and PTH have not supported the hypothesis that combination treatments with antiresorptive and anabolic agents would lead to synergistic activity. We hypothesized that combination treatment with a selective androgen receptor modulator (SARM), LGD-3303, and a bisphosphonate would be beneficial. In vitro competitive binding and transcriptional activity assays were used to characterize LGD-3303. LGD-3303 is a potent nonsteroidal androgen that shows little or no cross-reactivity with related nuclear receptors. Tissue selective activity of LGD-3303 was assessed in orchidectomized male rats orally administered LGD-3303 for 14 days. LGD-3303 increased the levator ani muscle weight above eugonadal levels but had greatly reduced activity on the prostate, never increasing the ventral prostate weight to >50% of eugonadal levels even at high doses. Ovariectomized female rats were treated with LGD-3303, alendronate, or combination treatment to study the effects on bone. DXA scans, histomorphometry, and biomechanics were performed. LGD-3303 increased muscle weight in females rats. In addition, LGD-3303 increased BMD and BMC at both cortical and cancellous bone sites. At cortical sites, the effects were caused in part by anabolic activity on the periosteal surface. At every measured site, combination treatment was as effective as either single agent and in some cases showed significant added benefit. LGD-3303 is a novel SARM with anabolic effects on muscle and cortical bone not observed with bisphosphonates. Combination therapy with LGD-3303 and alendronate had additive effects and may potentially be a useful therapy for osteoporosis and frailty.
Vajda
Eric G
EG
Discovery Research, Ligand Pharmaceuticals, San Diego, California 92121, USA. evajda@ligand.com
Hogue
Aimee
A
Griffiths
Kimberly N
KN
Chang
William Y
WY
Burnett
Kelven
K
Chen
Yanling
Y
Marschke
Keith
K
Mais
Dale E
DE
Pedram
Bijan
B
Shen
Yixing
Y
van Oeveren
Arjan
A
Zhi
Lin
L
López
Francisco J
FJ
Meglasson
Martin D
MD
D015502:Absorptiometry, Photon; D000726:Androgen Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001696:Biomechanical Phenomena / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D015519:Bone Density / Q000187:drug effects; D001851:Bone Diseases, Metabolic / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D004164:Diphosphonates / Q000494:pharmacology / Q000627:therapeutic use*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004967:Estrogens / Q000172:deficiency; D005260:Female; D005269:Femur / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008159:Lumbar Vertebrae / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008297:Male; D009919:Orchiectomy; D009929:Organ Size / Q000187:drug effects; D015675:Osteocalcin / Q000097:blood; D010052:Ovariectomy; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use; D015363:Quinolones / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D014158:Transcription, Genetic / Q000187:drug effects
D000726:Androgen Antagonists; D004164:Diphosphonates; D004967:Estrogens; D011758:Pyrroles; D015363:Quinolones; D015675:Osteocalcin; C535233:9-chloro-2-ethyl-1-methyl-3-(2,2,2-trifluoroethyl)-3H-pyrrolo(3,2-f)quinolin-7(6H)-one