Effects of the bisphosphonate, alendronate, on parturition in the rat.
Alendronate is a bisphosphonate which inhibits bone resorption. In female fertility studies in rats, dosages of 10 and 15 mg/kg/day produced physical signs of toxicity at parturition, including tremors, dystocia, and death in the dams and these were associated with neonatal deaths. These effects were associated with hypocalcemia in the dams but the fetuses were normocalcemic. There was no one critical period of treatment during gestation for these effects; they were instead proportional to length of treatment. Neonatal deaths were due to protracted deliveries rather than a direct effect of alendronate on the pups. Intravenous calcium supplementation (9.3 mg/dam) prevented the above-described adverse effects on dams and pups. In rats, fetal skeletal ossification is at its greatest rate in late gestation, and during this period free calcium is preferentially transported to the fetal compartment. The females meet this increased demand by calcium mobilization via increased bone resorption. We conclude that the maternotoxicity of alendronate in rats is due to the designed pharmacologic activity of this bisphosphonate; the drug prevents bone resorption and thereby denies the dam an important source of calcium at a time when fetal demand for this mineral is at its peak. The alendronate-induced hypocalcemia adversely affects parturition because uterine muscle contraction is a calcium-dependent process.
Minsker
D H
DH
Department of Safety Assessment, Merck Research Laboratories, West Point, Pennsylvania 19486.
Manson
J M
JM
Peter
C P
CP
D019386:Alendronate; D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D004164:Diphosphonates / Q000633:toxicity*; D005260:Female; D005298:Fertility / Q000187:drug effects; D006996:Hypocalcemia / Q000139:chemically induced; D007743:Labor, Obstetric / Q000187:drug effects*; D008431:Maternal-Fetal Exchange; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley
D004164:Diphosphonates; D002118:Calcium; D019386:Alendronate