Bisphosphonate
PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible
PREGNANCY SUMMARY
Alendronate does not cause structural anomalies in animals but does produce dose-related maternal and fetal toxicity. Several reports have described its use in or near pregnancy. Although one report did find significantly shorter gestations, reduced birth weight, and an increased rate of spontaneous abortions, these outcomes may have been due to the underlying maternal disease and/or the use of corticosteroids (1). Because the oral bioavailability is very low and the plasma clearance is rapid, clinically significant amounts may not cross the placenta. The drug is slowly released from bone; thus, the use before pregnancy may result in low-level, continuous exposure throughout gestation. The use of alendronate in women who may become pregnant or during pregnancy is not recommended. However, inadvertent exposure during early pregnancy does not appear to present a major risk to the embryo or fetus.
FETAL RISK SUMMARY
Bisphosphonates are synthetic analogs of pyrophosphate that bind to the hydroxyapatite found in bone. Alendronate, a specific inhibitor of osteoclast-mediated bone resorption, is indicated for the treatment and prevention of osteoporosis in postmenopausal women and men. Alendronate is also indicated for the treatment of Paget’s disease of bone and for glucocorticoid-induced osteoporosis. The oral bioavailability, relative to an IV reference dose, is very low with only about 0.6% absorbed under fasting conditions. Alendronate is not metabolized in animals or humans. Approximately 78% of the drug is bound to protein in human plasma. After an IV dose, the plasma half-life is about 1 hour (plasma concentrations fell by >95% within 6 hours). However, the terminal elimination half-life is >10 years because of its slow release from bone (2).
In pregnant rats, a dose 0.26 times the maximum recommended daily dose for Paget’s disease of 40 mg based on BSA (MRHD) caused decreased body weight in otherwise-normal pups. Decreased postimplantation survival occurred at 0.52 times the MRHD. With higher doses (2.6 times the MRHD), there was an increase in the incidence of incomplete fetal ossification in vertebrae, skull, and sternebrae. (Note: The daily doses for prevention and treatment of osteoporosis are 5 and 10 mg, respectively.) None of these adverse effects was observed in pregnant rabbits treated with doses up to 10.3 times the MRHD (2).
Delays and failure of delivery secondary to maternal hypocalcemia (both total and ionized calcium) were observed in pregnant rats at 3.9 times the MRHD. Normal calcium levels were measured in the fetuses. Late maternal pregnancy deaths also were observed at this dose. When the rats were treated from before mating through gestation, doses as small as 0.13 times the MRHD resulted in protracted parturition. Oral calcium supplementation did not prevent the hypocalcemia or prevent maternal and fetal deaths secondary to delays in delivery. However, IV calcium did prevent maternal, though not fetal, deaths (2,3).
In a study published in 1999, pregnant rats were treated with a daily SC dose of alendronate (0.1 mg/kg) during days 11–20 of pregnancy (4). Based on body weight, the dose was comparable to a human oral dose of 10 mg/day, but the systemic bioavailability was much higher than that obtained in humans. The gestational period was chosen because it covered the time of active bone development in rat fetuses. Alendronate passed through the placenta and accumulated in the fetuses. A significant increase in fetal bone calcium content (i.e., bone mass) with an accompanying significant decrease in bone marrow volume was found (4).
It is not known if alendronate crosses the placenta to the human fetus, but the molecular weight (about 325) is low enough that fetal exposure should be expected. Although the low maternal plasma concentration and short plasma half-life should reduce the amount of drug available for passage to the fetus, any drug that crosses the placenta probably will accumulate in fetal bones, as it does in rat fetuses.
A 2003 case report has described the use of alendronate in human pregnancy (5). A 49-year-old woman, who was amenorrheic and thought to be postmenopausal, was treated with oral alendronate 10 mg/day for osteoporosis. Treatment was begun before and continued throughout her gestation. An apparently normal female infant with a birth weight of 2390 g (50th percentile) was born at 36 weeks’ gestation. Laboratory tests were within normal limits. X-ray studies of the skull and wrists revealed normal bone structure and density without abnormal calcifications. At 1 year of age, the girl’s weight was 8 kg (10th percentile), her height was 73 cm (50th percentile), and her physical examination and psychomotor development were normal (5).
In a 2006 case series, 24 pregnancies were exposed to alendronate, 8 of the women took the drug 1–6 months before pregnancy, 15 before and during the first 3–8 weeks’, and 1 through week 21 (1). Because of the long elimination half-life, the three groups were combined and compared with 790 nonexposed controls. In the subjects, there were 19 liveborn infants with a median gestational age of 38 weeks (p = 0.001 vs. controls [40 weeks]). The median birth weight also was significantly lower in subjects, 2910 vs. 3290 g (p = 0.002), and there were more spontaneous abortions 20.8 vs. 7% (p = 0.026). However, 13 of the women were also taking corticosteroids. No major anomalies were observed in the subjects (1).
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) (6). 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 alendronate during nursing have been located. The molecular weight (about 325) is low enough for excretion into breast milk, but the low plasma concentrations and rapid plasma clearance suggest that minimal amounts will be excreted into milk. Moreover, since the oral bioavailability of this drug in the nonfasting state is negligible, systemic levels in a nursing infant should also be negligible (2).
References
1.Ornoy A, Wajnberg R, Diav-Citrin O. The outcome of pregnancy following pre-pregnancy or early pregnancy alendronate treatment. Reprod Toxicol 2006;22:578–9.
2.Product information. Fosamax. Merck & Co, 2003.
3.Minsker DH, Manson JM, Peter CP. Effects of the bisphosphonate, alendronate, on parturition in the rat. Toxicol Appl Pharmacol 1993;121:217–23.
4.Patlas N, Golomb G, Yaffe P, Pinto T, Breuer E, Ornoy A. Transplacental effects of bisphosphonates on fetal skeletal ossification and mineralization in rats. Teratology 1999;60:68–73.
5.Rutgers-Verhage AR, deVries TW, Torringa MJL. No effects of bisphosphonates on the human fetus. Birth Defects Res A Clin Mol Teratol 2003;67:203–4.
6.Djokanovic N, Klieger-Grossmann C, Koren G. Does treatment with bisphosphonates endanger the human pregnancy? J Obstet Gynaecol Can 2008;30:1146–8.