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Different Molecular Mechanisms Underlie Ethanol-Induced Bone Loss in Cycling and Pregnant Rats

Departments of Pharmacology and Toxicology (K.S., M.H., T.M.B., M.J.J.R.), Physiology and Biophysics (T.M.B.), Pediatrics (C.-H.J., P.S., C.K.L.), and Orthopedics (J.A., R.A.S., W.H.), College of Medicine, University of Arkansas for Medical Sciences, and Arkansas Children’s Nutrition Center (K.S., M.H., R.H., T.M.B., M.J.J.R.), Little Rock, Arkansas 72202

Address all correspondence and request for reprints to: Martin J. J. Ronis, Ph.D., Arkansas Children’s Nutrition Center, Slot 512–20B, 1120 Marshall Street, Little Rock, Arkansas 72202. E-mail: ronismartinj{at}uams.edu.

Chronic ethanol (EtOH) consumption can result in osteopenia. In the current study, we examined the modulation of EtOH-induced bone loss during pregnancy. Nonpregnant and pregnant dams were intragastrically infused either control or EtOH-containing diets throughout gestation (gestation d 5 through 20 or an equivalent period of 15 d) by total enteral nutrition. The effects of EtOH (8.5 to 14 g/kg/d) on tibial bone mineral density (BMD), mineral content (BMC), and bone mineral area were assessed at gestation d 20 via peripheral quantitative computerized tomography. EtOH caused a dose-dependent decrease in BMD and BMC without affecting bone mineral area. Trabecular BMD and BMC were significantly lower in EtOH-treated, nonpregnant dams, compared with pregnant cohorts at the same infused dose of EtOH and urinary ethanol concentrations. Static histomorphometric analysis of tibiae from pregnant rats after EtOH treatment showed decreased osteoblast and osteoid surface, indicating inhibited bone formation, whereas EtOH-treated cycling rats showed higher osteoclast and eroded surface, indicative of increased bone resorption. Circulating osteocalcin and 1,25-dihydroxyvitamin D₃ were lower in both EtOH-fed nonpregnant and pregnant rats. Gene expression of osteoclast markers, 70 kDa v-ATPase, and tartrate-resistant acid phosphatase were increased selectively in nonpregnant EtOH-treated rats but not pregnant rats. Moreover, only nonpregnant EtOH-fed rats showed induction in bone marrow receptor activator of nuclear factor-B ligand mRNA and decreased circulating 17ß-estradiol levels. Our data suggest that EtOH-induced bone loss in pregnant rats is mainly due to inhibited bone formation, whereas in nonpregnant rats, the data are consistent with increased osteoclast activation and bone resorption concomitant with decreased estradiol levels.

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