Alendronate administration and skeletal response during chronic alcohol intake in the adolescent male rat.
Alendronate is an aminobisphosphonate that inhibits bone resorption in osteoporotic humans and rats but does not induce osteomalacia. Several bisphosphonates, including alendronate, also have direct positive actions on osteoblasts, bone formation, and mineralization. We studied the effects of alendronate on skeletal development in adolescent male rats during chronic alcohol intake. Four groups of age- and weight-matched male Sprague-Dawley rats (35 days of age) were fed the Lieber-DeCarli diet containing 36% of calories as EtOH (E), the EtOH diet plus 60 mg/kg alendronate (EA) every other day intraperitoneally (ip), an isocaloric diet (I), or the isocaloric diet plus 60 mg/kg alendronate (IA) every other day ip. Body weight, femur length, serum levels of osteocalcin (OC), insulin-like growth factor 1 (IGF-1), testosterone, and luteinizing hormone (LH); femur distal metaphyseal and middiaphyseal bone mineral density (BMD) and tibial metaphyseal gene expression for alpha-1-type I collagen (Col I), OC, and bone alkaline phosphatase (AP); and femur strength by four-point bending to failure were measured after 28 days of feeding and alendronate injections. Serum alcohol levels at death were 156 +/- 13 mg/dl (E) and 203 +/- 40 mg/dl (EA). Alendronate given to alcohol-fed rats increased metaphyseal BMD by more than 3-fold over rats fed alcohol alone. Alendronate given to isocaloric pair-fed rats increased metaphyseal BMD by more than 2.5-fold over rats fed the isocaloric diet alone. Cortical BMD was reduced by alcohol but was increased by alendronate. Alcohol consumption reduced serum IGF-1 levels, and alendronate increased IGF-1 levels in alcohol-fed rats. Serum OC, testosterone, and LH were unaffected by alcohol and alendronate. Quantitative dot blot hybridization using rat complementary DNA (cDNA) probes and normalization against 18S subunit ribosomal RNA (rRNA) levels revealed no changes in tibial metaphyseal gene expression for type I collagen, osteocalcin, or alkaline phosphatase. Alcohol significantly reduced the biomechanical properties of the femurs that were partially compensated by alendronate. Chronic alcohol consumption uncouples formation from ongoing resorption, and resorption is inhibited by alendronate. However, alendronate's positive effects on osteoblast-mediated mineralization during chronic alcohol consumption point to the potential use of bisphosphonates in the treatment of decreased bone formation secondary to alcohol-induced diminished osteoblast function.
Wezeman
F H
FH
Department of Orthopedic Surgery and Rehabilitation, Loyola University Stritch School of Medicine, Maywood, Illinois 60153, USA.
Emanuele
M A
MA
Moskal
S F
SF
Steiner
J
J
Lapaglia
N
N
D000437:Alcoholism / Q000188:drug therapy / Q000503:physiopathology; D019386:Alendronate / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001696:Biomechanical Phenomena; D015519:Bone Density / Q000187:drug effects; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D003094:Collagen / Q000032:analysis / Q000235:genetics; D000431:Ethanol / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D005269:Femur / Q000187:drug effects / Q000254:growth & development / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D015675:Osteocalcin / Q000097:blood / Q000235:genetics; D010024:Osteoporosis / Q000188:drug therapy / Q000503:physiopathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012741:Sexual Maturation; D013739:Testosterone / Q000097:blood; D015430:Weight Gain / Q000187:drug effects
D012333:RNA, Messenger; D015675:Osteocalcin; D000431:Ethanol; D013739:Testosterone; D007334:Insulin-Like Growth Factor I; D007986:Luteinizing Hormone; D003094:Collagen; D000469:Alkaline Phosphatase; D019386:Alendronate