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.

Nyckelord

Animals

Apoptosis

drug effects

Biomechanics

Body Weight

drug effects

Bone Development

drug effects

Brain

drug effects

growth & development

Cartilage

drug effects

Cell Proliferation

drug effects

Chondrocytes

cytology

drug effects

Collagen Type X

metabolism

Feeding Behavior

drug effects

Femur

drug effects

physiology

Growth Plate

cytology

drug effects

Insulin-Like Growth Factor I

metabolism

Liver Function Tests

Male

Organ Size

drug effects

Rats

Rats

Sprague-Dawley

Tamoxifen

blood

pharmacology

Testis

drug effects

growth & development

Tomography

X-Ray Computed

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