Tamoxifen impairs both longitudinal and cortical bone growth in young male rats.
Tamoxifen (Tam) has been used experimentally to treat boys with gynecomastia and girls with McCune-Albright syndrome. This drug was recently shown to inhibit the growth of cultured fetal rat metatarsal bones and thus might also affect bone growth in vivo. Four-week-old Sprague-Dawley rats were gavaged daily with vehicle alone (peanut oil), Tam (40 mg/kg/d; 1 or 4 wk), or estradiol (40 microg/kg/d; 4 wk). Five of the 10 rats in each group were killed after 4 wk and the other five after 14 wk of recovery. Bone growth was followed by repeat DXA scans, whereas other bone parameters and spine length were evaluated by pQCT and X-ray at the time of death. Four-week Tam treatment significantly decreased body weight, nose-anus distance, spinal and tibial bone lengths, trabecular BMD, cortical periosteal circumference, and bone strength and also reduced serum IGF-I levels (424 +/- 54 versus 606 +/- 53 ng/ml in control; p < 0.05). Analysis of the tibial growth plate of treated rats showed elevated chondrocyte proliferation (BrdU) and apoptosis (TUNEL), as well as decreases in the number of hypertrophic chondrocytes and in the size of terminal hypertrophic chondrocytes. Despite a complete catch-up of body weight after 14 wk of recovery, the tibia was still shorter (p < 0.001) and its cortical region was smaller. We conclude that, when administered at a clinically relevant dose, Tam causes persistent retardation of longitudinal and cortical radial bone growth in young male rats. Our findings suggest that this inhibition results from local effects on the growth plate cartilage and systemic suppression of IGF-I production. Based on these rat data, we believe that Tam, if given to growing individuals, might compromise cortical bone growth, bone strength, and adult height.
Karimian
Elham
E
Pediatric Endocrinology Unit, Department of Woman and Child Health, Karolinska Institutet, Stockholm, Sweden. Elham.Karimian@ki.se
Chagin
Andrei S
AS
Gjerde
Jennifer
J
Heino
Terhi
T
Lien
Ernst A
EA
Ohlsson
Claes
C
Sävendahl
Lars
L
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001696:Biomechanical Phenomena; D001835:Body Weight / Q000187:drug effects; D001846:Bone Development / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000254:growth & development; D002356:Cartilage / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019902:Chondrocytes / Q000166:cytology / Q000187:drug effects; D024121:Collagen Type X / Q000378:metabolism; D005247:Feeding Behavior / Q000187:drug effects; D005269:Femur / Q000187:drug effects / Q000502:physiology; D006132:Growth Plate / Q000166:cytology / Q000187:drug effects; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008111:Liver Function Tests; D008297:Male; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013629:Tamoxifen / Q000097:blood / Q000494:pharmacology*; D013737:Testis / Q000187:drug effects / Q000254:growth & development; D014057:Tomography, X-Ray Computed
D024121:Collagen Type X; D013629:Tamoxifen; D007334:Insulin-Like Growth Factor I