The skeletal effects of glucocorticoid excess override those of orchidectomy in mice.
Hypogonadism has been implicated as a contributing factor in glucocorticoid-induced osteoporosis, but evidence for this is limited. Hypogonadism and glucocorticoid excess both cause bone loss, but the cellular mechanisms responsible are distinct. Loss of gonadal steroids causes an increase in bone remodeling by up-regulating osteoblastogenesis and osteoclastogenesis. Glucocorticoid excess, conversely, suppresses remodeling by down-regulating osteoblastogenesis and osteoclastogenesis. Nonetheless, both conditions increase osteoblast apoptosis and decrease osteoclast apoptosis, and both cause bone loss due to an undersupply of osteoblasts relative to the need for cavity repair. To investigate their interactions, we compared the effects of orchidectomy, glucocorticoid excess, or both combined in mice. After 28 d, serum unbound testosterone concentration and seminal vesicle weight were not diminished when prednisolone was administered alone. Vertebral bone mineral density and compression strength decreased to the same extent in animals receiving prednisolone or after orchidectomy, but the changes were not additive. Orchidectomy induced the expected up-regulation of osteoblast and osteoclast progenitors, but these changes were prevented in orchidectomized mice simultaneously receiving glucocorticoids. Likewise, the increase in cancellous osteoid, osteoblasts, osteoclasts, bone formation, and activation frequency caused by orchidectomy were prevented by prednisolone. The prevalence of osteoblast apoptosis increased in the mice receiving prednisolone or after orchidectomy, but the increases were not additive. These data demonstrate that hypogonadism does not occur in or contribute to glucocorticoid-induced osteoporosis and that the adverse skeletal effects of glucocorticoid excess override those of orchidectomy.
Weinstein
Robert S
RS
Center for Osteoporosis and Metabolic Bone Diseases, Department of Internal Medicine, Central Arkansas Veterans Healthcare System, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205-7199, USA. weinsteinroberts@uams.edu
Jia
Dan
D
Powers
Cara C
CC
Stewart
Scott A
SA
Jilka
Robert L
RL
Parfitt
A Michael
AM
Manolagas
Stavros C
SC
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D015519:Bone Density / Q000187:drug effects; D001842:Bone and Bones / Q000187:drug effects* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D019245:Compressive Strength; D005938:Glucocorticoids / Q000009:adverse effects*; D008297:Male; D051379:Mice; D009919:Orchiectomy; D009929:Organ Size / Q000187:drug effects; D010006:Osteoblasts / Q000473:pathology; D010010:Osteoclasts / Q000473:pathology; D010024:Osteoporosis / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D011239:Prednisolone / Q000009:adverse effects*; D012669:Seminal Vesicles / Q000473:pathology; D013131:Spine / Q000378:metabolism / Q000503:physiopathology
D005938:Glucocorticoids; D011239:Prednisolone