Bisphosphonate
PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Low Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible
PREGNANCY SUMMARY
Although the dose comparisons were based on body weight, etidronate did not cause developmental toxicity in animals at doses that were close to those used in humans. Two reports have described the use of bisphosphonates before or during six human pregnancies. Because the oral bioavailability is low and the plasma clearance is rapid, clinically significant amounts of etidronate may not cross the human placenta. Nonetheless, the drug is slowly released from bone over weeks to years. 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
Etidronate (EHDP), a hydrophilic bisphosphonate, is a synthetic analog of pyrophosphate that binds to the hydroxyapatite found in bone to inhibit bone resorption. Etidronate is indicated for the treatment of symptomatic Paget’s disease of bone and in the prevention and treatment of heterotopic ossification after total hip replacement or because of spinal cord injury. Other agents in this pharmacologic class are alendronate, ibandronate, pamidronate, risedronate, tiludronate, and zoledronic acid. Only about 3% of an oral dose is absorbed into the systemic circulation. Etidronate is not metabolized. The plasma half-life ranges from 1 to 6 hours. About half of the absorbed drug is distributed to bone from which it is slowly released over a prolonged period. Although the elimination half-life from bone is not known with certainty, the clearance from bone in animals is up to 165 days (1).
Reproduction studies have been conducted with etidronate in rats and rabbits. In pregnant rats and rabbits, doses 5–20 times the human clinical dose based on body weight (HCD) did not cause teratogenic or other adverse effects in the offspring. At doses 15–60 times the HCD, etidronate exposure in pregnant rats was associated with skeletal anomalies in the offspring. These defects were thought to be secondary to the action of etidronate on bone. Decreased live births were observed with maternally toxic doses 25–300 times the HCD (1). Shepard reviewed four animal studies in which etidronate was given orally, subcutaneously, or intraperitoneally to mice, rats, and rabbits during gestation (2). Skeletal abnormalities were produced with high doses, but no other developmental toxic effects were observed.
No evidence of carcinogenic effects was observed in long-term studies in rats (1). Studies for mutagenic and clastogenic effects apparently have not been conducted.
It is not known if etidronate crosses the human placenta. The relatively low molecular weight (250), the absence of metabolism, and the prolonged clearance from bone all suggest that exposure of the embryo–fetus will occur. The relatively short plasma half-life, low lipid solubility, and oral bioavailability should limit this exposure.
A 1992 case report described the in utero treatment of a fetus with etidronate early in the 3rd trimester (3). Based on ultrasonography and the mother’s obstetric history, a presumptive diagnosis of a rare disorder, idiopathic arterial calcification of infancy (IACI), was made in the fetus at 29 weeks’ gestation. The fetus was treated with two courses of etidronate by percutaneous umbilical vein puncture. Fetal distress occurred 1 week later and the 1700-g female infant was delivered by emergency cesarean section with Apgar scores of 2 and 6 at 1 and 5 minutes, respectively. IACI was confirmed in the neonate 1 week after birth. The infant was treated with etidronate over the next several months. Radiographs of her skeleton showed severe growth plate malformations resembling rickets that were thought to be secondary to etidronate. The infant died at 7.5 months of age despite aggressive therapy for prematurity and her disease (3).
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) (4). 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 etidronate during lactation have been located. The molecular weight (250) and the lack of metabolism suggest that the drug will be excreted into breast milk, but the low plasma concentrations and relatively short plasma half-life (1–6 hours) suggest that minimal amounts will be excreted into milk. Moreover, the oral bioavailability of etidronate, at least in adults, is only 3%. Although the effect of exposure on a nursing infant is unknown, it appears to be negligible.
References
1.Product information. Didronel. Procter & Gamble Pharmaceuticals, 2006.
2.Shepard TH. Catalog of Teratogenic Agents. 10th ed. Baltimore, MD: The Johns Hopkins University Press, 2001:211–2.
3.Bellah RD, Zawodniak L, Librizzi RJ, Harris MC. Idiopathic arterial calcification of infancy: prenatal and postnatal effects of therapy in an infant. J Pediatr 1992;121:930–3.
4.Djokanovic N, Klieger-Grossmann C, Koren G. Does treatment with bisphosphonates endanger the human pregnancy? J Obstet Gynaecol Can 2008;30:1146–8.