Patlas N, Golomb G, Yaffe P, Pinto T, Breuer E, Ornoy A
Department of Anatomy and Cell Biology, Faculty of Medicine, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Teratology. 1999 Aug;60(2):68-73. doi: 10.1002/(SICI)1096-9926(199908)60:2<68::AID-TERA10>3.0.CO;2-H.
Bisphosphonates are clinically used mainly to reduce bone resorption. We studied the transplacental effects of two bisphosphonates on the fetal skeleton in rats. Pregnant rats were treated during days 11-20 of pregnancy with daily subcutaneous injections of 0.1 mg/kg of alendronate or a newly synthesized bisphosphonate, VS-b6. This period of pregnancy was chosen because the active development of bones from mesenchyme through cartilaginous models occurs during that time. Histological examination of midlongitudinal sections of the 21-day-old fetuses showed an increase in the amount of diaphyseal bone trabeculae with slight shortening of the diaphysis in the experimental fetuses, in comparison to controls. Computerized histomorphometric studies similarly showed an increase in the amount of diaphyseal bone trabeculae with a concomitant decrease in bone marrow volume, but no change in cartilage volume. In addition, chemical analysis of the fetal bones showed an increase in calcium content in the treated fetuses. 14C-alendronate was shown to pass through the rat placenta and accumulate in the fetuses, most probably in their bones. This is presumed because bisphosphonates are known to accumulate in bone, being stored there for long periods of time. It is important, in light of our results, to give careful consideration to the treatment of women with bisphosphonates at childbearing age, whenever this is needed.
双膦酸盐类药物在临床上主要用于减少骨吸收。我们研究了两种双膦酸盐类药物对大鼠胎儿骨骼的经胎盘影响。在妊娠第11 - 20天，对怀孕大鼠每日皮下注射0.1 mg/kg阿仑膦酸钠或一种新合成的双膦酸盐VS - b6进行治疗。选择这个孕期阶段是因为在此期间骨骼从间充质通过软骨模型进行活跃发育。与对照组相比，对21日龄胎儿的中纵切面进行组织学检查发现，实验胎儿骨干骨小梁数量增加，骨干略有缩短。计算机化组织形态计量学研究同样显示骨干骨小梁数量增加，同时骨髓体积减少，但软骨体积无变化。此外，对胎儿骨骼的化学分析表明，经治疗的胎儿钙含量增加。14C标记的阿仑膦酸钠显示可穿过大鼠胎盘并在胎儿体内蓄积，很可能蓄积在其骨骼中。推测如此是因为已知双膦酸盐类药物会在骨骼中蓄积，并在那里长期储存。鉴于我们的研究结果，在需要时，对于育龄期使用双膦酸盐类药物治疗的女性，应予以谨慎考虑。
