Bisphosphonate
PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible
PREGNANCY SUMMARY
The use of risedronate before or during pregnancy has been described, but the data are very limited. No drug-induced toxicity was seen in the offspring. Although the animal data suggest risk of developmental toxicity, the near absence of human pregnancy experience prevents an assessment of the embryo–fetal risk. However, the very long elimination half-life from bone indicates that women treated with risedronate will have detectable concentrations of the drug for a prolonged interval. 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. Thus, administration before pregnancy may result in low-level, continuous exposure throughout gestation. The use of etidronate in women who may become pregnant or during pregnancy is not recommended. However, based on the animal and limited human data, inadvertent exposure during early pregnancy does not appear to represent a major risk to the embryo–fetus.
FETAL RISK SUMMARY
Bisphosphonates are synthetic analogs of pyrophosphate that bind to the hydroxyapatite found in bone. Other agents in this class include alendronate, etidronate, ibandronate, pamidronate, tiludronate, and zoledronic acid. Risedronate, a specific inhibitor of osteoclast-mediated bone resorption, is indicated for the treatment and prevention of osteoporosis in postmenopausal women. It also is indicated for the prevention and treatment of glucocorticoid-induced osteoporosis in men and women, and in the treatment of Paget’s disease of bone (osteitis deformans). Risedronate is not metabolized, and plasma protein binding is minimal (about 24%). The elimination half-life is biphasic with an initial serum half-life of about 1.5 hours. The very long terminal half-life (480 hours) is thought to be secondary to its slow dissociation from the surface of bone. The mean absolute oral bioavailability is 0.63% and is reduced even further by meals. Steady state serum drug concentrations are obtained within 57 days of daily dosing (1).
Reproduction studies have been conducted in rats and rabbits. Treatment during mating and gestation with doses as low as the maximum recommended human dose of 30 mg/day based on BSA (MRHD) resulted in periparturient hypocalcemia and mortality in pregnant rats. This same dose was associated with a low incidence of cleft palate in fetuses. During gestation, doses as low as about 5.2 times the MRHD resulted in decreased survival of neonates. At 26 times the MRHD, the body weight of surviving neonates decreased. A significant increase in the number of fetuses with incomplete ossification of sternebrae or skull was observed at about 2.3 times the MRHD, and both incomplete ossification and unossified sternebrae were increased at about 5.2 times the MRHD. In rabbits, no significant fetal ossification effects were observed at doses up to 6.7 times the MRHD. At this dose, however, 1 of 14 litters was aborted and 1 litter delivered prematurely (1).
Long-term studies in rats revealed no evidence of carcinogenesis. In addition, various assays have found no evidence of mutagenesis when nontoxic doses were used. Risedronate, however, did impair fertility in male rats and dogs at doses as low as about 5.2 and 8 times the MRHD, respectively. In female rats, ovulation was inhibited at a dose about 5.2 times the MRHD, and decreased implantation was noted at a dose about 2.3 times the MRHD (1).
It is not known if risedronate crosses the human placenta. The molecular weight (about 350 for the hemi-pentahydrate form), low protein binding, and lack of metabolism suggest that the drug will cross to the embryo–fetus. The amount available for diffusion across the placenta during treatment should be minimal because of the low oral bioavailability and short serum elimination half-life. When treatment has been discontinued, the amount of drug available for diffusion during the prolonged bone elimination should be even lower, but the drug will be present at the maternal–fetal interface for months or longer.
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 risedronate during human lactation have been located. The molecular weight (about 350 for the hemi-pentahydrate form), low protein binding (about 24%), lack of metabolism, and very long bone elimination half-life (480 hours) suggest that some drug will be excreted into milk. However, the amount excreted into milk during human treatment should be minimal because of the low oral bioavailability (0.63%) and short serum elimination half-life (about 1.5 hours). When treatment has been discontinued, the amount of drug available for excretion during the prolonged bone elimination should be even lower, although excretion into milk could occur for several months. The effect of this exposure on a nursing infant is unknown but is probably negligible.
References
1.Product information. Actonel. Procter & Gamble Pharmaceuticals, 2005.
2.Djokanovic N, Klieger-Grossmann C, Koren G. Does treatment with bisphosphonates endanger the human pregnancy? J Obstet Gynaecol Can 2008;30:1146–8.