Aromatase inhibition impairs skeletal modeling and decreases bone mineral density in growing male rats.
Aromatization of androgens into estrogens may explain some of the skeletal action of androgens. We examined the effect of the aromatase inhibitor Vorozole (VOR) on skeletal growth and mineral accumulation in growing 6-week-old male Wistar rats. Rats were either Sham-operated (Sham) or Orchidectomized (Orch) and treated with or without the aromatase inhibitor VOR. One Sham-operated group was killed at Baseline (Base); the four other groups (Sham, Sham + VOR, Orch, Orch + VOR) were killed 18 weeks after surgery. As expected, all groups gained body weight, but body weight gain was significantly (-25%) lower in Orch, Orch + VOR, and Sham + VOR. Both bone formation, as assessed by serum osteocalcin, and bone resorption, as assessed by urinary (deoxy)pyridinoline, decreased significantly in all groups compared with Base. Orchidectomy resulted in a relative increase of biochemical markers of bone formation and resorption compared with Sham. Treatment with VOR, however, resulted only in a very moderate increase of (deoxy)pyridinoline compared with Sham. As expected, femoral length increased compared with Base, but orchidectomy reduced the relative growth of the femur whereas VOR did not influence femoral length. Ex vivo, densitometric and geometric properties of the femora were evaluated by peripheral computerized quantitative tomography (pQCT) and dual-energy x-ray absorptiometry (DXA). The lumbar vertebrae were measured by DXA. At the end of the experimental period, volumetric trabecular bone mineral density (vTBMD) measured at the distal end of the femur was significantly lower not only in both Orch groups but also in Sham + VOR. The decrease of cancellous bone density in Sham + VOR was lower than in the orchidectomized animals. A relative decrease of femoral inner and outer diameters compared with Sham and Base was observed in both Orch groups and in Sham + VOR, suggesting that both orchidectomy and VOR-treatment inhibited periosteal bone formation and endosteal bone resorption. Only orchidectomy, however, resulted in a decrease of cortical thickness. Bone area, mineral content, and density of both femora and lumbar vertebrae, measured by DXA, were decreased to a similar extent by VOR and Orch (bone mineral content of the femur was 467 +/- 18 mg in Orch and 461 +/- 10 mg in Sham +/- VOR vs. 521 +/- 11 mg in Sham; P < 0.001). In conclusion, treatment with the aromatase inhibitor VOR impairs body weight gain and skeletal modeling and decreases bone mineral density. Aromatase inhibition had similar final effects on bone mass and size as castration, but with less marked effects on bone turnover.
Vanderschueren
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D
Laboratorium of Experimental Medicine and Endocrinology (LEGENDO), Onderwijs en Navorsing, Gasthuisberg, Leuven, Belgium.
van Herck
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E
Nijs
J
J
Ederveen
A G
AG
De Coster
R
R
Bouillon
R
R
D015502:Absorptiometry, Photon; D000375:Aging; D000818:Animals; D047072:Aromatase Inhibitors; D001835:Body Weight; D015519:Bone Density / Q000187:drug effects*; D001846:Bone Development / Q000187:drug effects*; D016723:Bone Remodeling / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005269:Femur; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D009919:Orchiectomy; D051381:Rats; D017208:Rats, Wistar; D012016:Reference Values; D014230:Triazoles / Q000494:pharmacology*
D047072:Aromatase Inhibitors; D004791:Enzyme Inhibitors; D014230:Triazoles; C060523:vorozole; D007334:Insulin-Like Growth Factor I