Bisphosphonate
PREGNANCY RECOMMENDATION: No Human Data—Animal Data Suggest Moderate Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible
PREGNANCY SUMMARY
No reports describing the use of tiludronate in human pregnancy have been located. Developmental toxicity (growth restriction, structural anomalies, and death) at doses close to those used in humans was observed in three animal species, but the maternal toxicity evident in two of the species prevents a better assessment of the animal embryo–fetal toxicity. The complete lack of human pregnancy experience with tiludronate and the very limited human data for the bisphosphonate class prevent further assessment of the risk. The amount of drug retained in bone and eventually released back into the systemic circulation is directly related to the dose and duration of treatment. Because tiludronate probably crosses the placenta, treatment of the mother before conception could result in continuous exposure of the embryo and fetus to an unknown amount of drug. Therefore, the use of tiludronate is not recommended in women who may become pregnant or during pregnancy. There is a theoretical risk of fetal harm (e.g., skeletal and other abnormalities) (1), but the magnitude of this risk cannot be estimated at the present time. Infants exposed in utero to tiludronate should be monitored for hypocalcemia during the first few days after birth.
FETAL RISK SUMMARY
Tiludronate is a bisphosphonate in the same class as alendronate, etidronate, ibandronate, pamidronate, risedronate, and zoledronic acid. It is indicated for the treatment of Paget’s disease of bone (osteitis deformans). Tiludronate undergoes little, if any, metabolism. The plasma elimination half-life is about 150 hours, but the elimination rate from bone is unknown (1).
Reproduction studies have been conducted in mice, rats, and rabbits. In mice during organogenesis, a dose 7 times the 400 mg/day human dose based on BSA (HD) caused maternal toxicity (decreased body weight gain) and embryo–fetal developmental toxicity (increased postimplantation loss, decreased number of fetuses per dam, and decreased fetal body weight). A low incidence of malformations of the paw (shortened or missing digits, blood blisters between or in place of digits) was seen in one litter. Similar effects, including maternal toxicity but not fetal malformations, were observed in rats dosed at 10 times the HD. When rats were given doses 2 times the HD from day 15 of gestation to day 26 postpartum, protracted parturition and maternal death, presumably due to hypocalcemia, were observed. In rabbits during organogenesis, doses 2 and 5 times the HD caused dose-related scoliosis that was thought to be attributable to the pharmacologic properties of the drug (1).
Tiludronate was not genotoxic in several assays. The drug also had no effect on male or female rat fertility at doses up to twice the HD (1).
It is not known if tiludronate crosses the human placenta. The molecular weight (about 326 for the free acid), prolonged plasma elimination half-life (150 hours), and lack of metabolism suggest that active drug will cross to the embryo–fetus.
A 2008 review described 51 cases of exposure to bisphosphonates before or during pregnancy: alendronate (N = 32), pamidronate (N = 11), etidronate (N = 5), risedronate (N = 2), and zoledronic acid (N = 1) (2). The authors concluded that although these drugs may affect bone modeling and development in the fetus, no such toxicity has yet been reported.
BREASTFEEDING SUMMARY
No reports describing the use of tiludronate during lactation have been located. The molecular weight (about 326 for the free acid), prolonged plasma elimination half-life (150 hours), and lack of metabolism suggest that active drug will be excreted into breast milk. Although the oral bioavailability in infants differs from that of adults, the very low adult oral bioavailability (<1% with food) and the binding of tiludronate by the calcium in milk suggest that the amount absorbed by the infant will be clinically insignificant. Thus, breastfeeding is probably compatible with tiludronate treatment.
References
1.Product information. Skelid. Sanofi-Synthelabo, 2003.
2.Djokanovic N, Klieger-Grossmann C, Koren G. Does treatment with bisphosphonates endanger the human pregnancy? J Obstet Gynaecol Can 2008;30:1146–8.