title: Testosterone dose dependently prevents bone and muscle loss in rodents after spinal cord injury.
abstract: Androgen administration protects against musculoskeletal deficits in models of sex-steroid deficiency and injury/disuse. It remains unknown, however, whether testosterone prevents bone loss accompanying spinal cord injury (SCI), a condition that results in a near universal occurrence of osteoporosis. Our primary purpose was to determine whether testosterone-enanthate (TE) attenuates hindlimb bone loss in a rodent moderate/severe contusion SCI model. Forty (n=10/group), 14 week old male Sprague-Dawley rats were randomized to receive: (1) Sham surgery (T9 laminectomy), (2) moderate/severe (250 kdyne) SCI, (3) SCI+Low-dose TE (2.0 mg/week), or (4) SCI+High-dose TE (7.0 mg/week). Twenty-one days post-injury, SCI animals exhibited a 77-85% reduction in hindlimb cancellous bone volume at the distal femur (measured via μCT) and proximal tibia (measured via histomorphometry), characterized by a >70% reduction in trabecular number, 13-27% reduction in trabecular thickness, and increased trabecular separation. A 57% reduction in cancellous volumetric bone mineral density (vBMD) at the distal femur and a 20% reduction in vBMD at the femoral neck were also observed. TE dose dependently prevented hindlimb bone loss after SCI, with high-dose TE fully preserving cancellous bone structural characteristics and vBMD at all skeletal sites examined. Animals receiving SCI also exhibited a 35% reduction in hindlimb weight bearing (triceps surae) muscle mass and a 22% reduction in sublesional non-weight bearing (levator ani/bulbocavernosus [LABC]) muscle mass, and reduced prostate mass. Both TE doses fully preserved LABC mass, while only high-dose TE ameliorated hindlimb muscle losses. TE also dose dependently increased prostate mass. Our findings provide the first evidence indicating that high-dose TE fully prevents hindlimb cancellous bone loss and concomitantly ameliorates muscle loss after SCI, while low-dose TE produces much less profound musculoskeletal benefit. Testosterone-induced prostate enlargement, however, represents a potential barrier to the clinical implementation of high-dose TE as a means of preserving musculoskeletal tissue after SCI.
authors.affiliation: 1 VA Medical Center, Research Service, VA Medical Center , Gainesville, Florida.
authors.forename: Joshua F
authors.initials: JF
authors.lastname: Yarrow
authors.forename: Christine F
authors.initials: CF
authors.lastname: Conover
authors.forename: Luke A
authors.initials: LA
authors.lastname: Beggs
authors.forename: Darren T
authors.initials: DT
authors.lastname: Beck
authors.forename: Dana M
authors.initials: DM
authors.lastname: Otzel
authors.forename: Alexander
authors.initials: A
authors.lastname: Balaez
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Combs
authors.forename: Julie R
authors.initials: JR
authors.lastname: Miller
authors.forename: Fan
authors.initials: F
authors.lastname: Ye
authors.forename: J Ignacio
authors.initials: JI
authors.lastname: Aguirre
authors.forename: Kathleen G
authors.initials: KG
authors.lastname: Neuville
authors.forename: Alyssa A
authors.initials: AA
authors.lastname: Williams
authors.forename: Bryan P
authors.initials: BP
authors.lastname: Conrad
authors.forename: Chris M
authors.initials: CM
authors.lastname: Gregory
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Wronski
authors.forename: Prodip K
authors.initials: PK
authors.lastname: Bose
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Borst
mesh_terms: D000728:Androgens / Q000008:administration & dosage*; D000818:Animals; D001284:Atrophy / Q000517:prevention & control; D015519:Bone Density / Q000187:drug effects; D001842:Bone and Bones / Q000187:drug effects* / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000473:pathology; D011467:Prostate / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013119:Spinal Cord Injuries / Q000150:complications*; D013739:Testosterone / Q000008:administration & dosage*
chemical_list: D000728:Androgens; D013739:Testosterone