1- General
practitioner, Pondok Indah Hospital - Pondok Indah, Jakarta, Indonesia.
2- Department
of Child Health, Faculty of Medicine Universitas Indonesia - dr. Cipto
Mangunkusumo General Hospital, Jakarta, Indonesia.
3- Pediatric
endocrinologist, Pondok Indah Hospital - Pondok Indah, Jakarta, Indonesia
Background: Zoledronic acid, a bisphosphonate, is currently
used to treat osteogenesis imperfecta (OI). Elevated liver enzymes or
hepatotoxicity induced by zoledronic acid infusion have been rarely reported,
especially in a neonate with OI.
Aims: This report aims to describe the case of a neonate with OI who developed transiently elevated liver enzymes accompanied by a fever after zoledronic acid treatment.
Clinical Descriptions: A one-month-old neonate diagnosed with OI in utero
was scheduled for the first treatment of zoledronic acid. Before zoledronic
acid was administered, liver enzymes were normal. Eighteen hours following the
zoledronic acid infusion (0.025 mg/kg intravenously for 30 minutes slow
infusion), the patient developed a fever. At 48 hours after treatment, serum
alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels
increased by 2.8 and 3.7 times, respectively, without jaundice. On day 5, the
AST level decreased to 1.7 times from baseline, but not the ALT level (4.0
times from baseline). Paracetamol was administered only when the baby had a
fever.
Conclusion: Potential liver injury as an adverse effect following zoledronic acid treatment in a neonate with OI should not be overlooked.
Keywords: adverse effect, bisphosphonate, liver enzyme, osteogenesis imperfecta, zoledronic acid
INTRODUCTION
Osteogenesis imperfecta (OI), or brittle bone disease,
is a connective tissue disorder with a wide range of clinical manifestations
ranging from lethal in the perinatal period to a mild clinical form. OI has a
triad of clinical symptoms: fragile bones, blue sclerae, and early deafness.
The reported incidence of OI varies across studies. It is estimated to be between
6 and 7 in 100,000 live births, without significant differences between different
races. About 80–90% of OI patients are known to have COL1A1 or COL1A2 mutations
that disrupt polypeptide chains pro alpha 1 and pro alpha 2 of type I collagen
synthesis, as they play a significant role as structural proteins in the human
body.1,2
Currently, no medical or surgical treatment
can cure OI. Supportive treatment should be carried out to minimize the risk of
fracture and disability. In addition to orthopedic management, bisphosphonates,
a class of drugs used to treat osteoporosis, have been used to treat OI. This
class of drug may reduce osteoclast activity while extending the life of
osteoblasts.1,2 These drugs have been
reported to be safe. Bisphosphonate treatment in children and adolescents has
been described with satisfactory outcomes.3 Cases of mild
zoledronate-induced hepatotoxicity have been previously reported in adults with
Paget’s disease and glucocorticoid-induced osteoporosis,4,5 but not in a neonate
with OI. This case report aims to describe a transient hepatic injury as a
possible adverse effect following zoledronic acid administration.
METHODOLOGY
This is a case
report and the authors certify that they have obtained all appropriate patient
consent forms. In the form, the patient’s parents have given their consent for
clinical information to be reported in this study. The patients’ parents
understand that name and initials will not be published. Based on the hospital
policy, neither institutional ethical approval nor specific permission is not
required for reporting case reports or series.
CLINICAL
DESCRIPTION
A baby boy was born by cesarean section at 38 weeks of
gestation due to premature rupture of membranes and breech presentation. The
mother was a healthy 35-year-old woman, and the father was 37 years old; there
was no history of consanguinity. Routine antenatal care was performed. At 23
weeks of gestation, fetal ultrasonography revealed that the fetus’s femur
length was shorter than normal; thus, a feto-maternal obstetrician was
consulted. Fetal ultrasonography at 25 weeks of gestation found multiple
fractures on both femurs, which suggested OI. Upon delivery, both lower
extremities were noticeably bowed and short, with “frog-like” positions. The
baby is the second child of the family; none of the family members have the
same symptoms.
At one day old, a full-body x-ray was performed that revealed bilateral distal femur fractures. Thus, an orthopedic doctor was consulted, and bilateral long casts were fitted for two weeks. At 25 days old, right arm movement suddenly decreased, and the baby looked to be in pain when he was handled. A second full-body x-ray revealed bilateral humeral fractures, a right femur refracture, and a left tibial fracture (Figure 1). Subsequent management consisted of bilateral upper and lower extremity casts for two weeks. Zoledronic acid treatment was scheduled.
At one month of age, zoledronic acid was administered. Before zoledronic acid was administered, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels are normal (ALT: 18 U/L, AST: 39 U/L). Eighteen hours following zoledronic acid infusion (0.025 mg/kg intravenously for 30 minutes slow infusion), the patient developed a fever. Forty-eight hours after treatment, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels increased by 3.7 and 2.8 times (ALT : 67 U/L, AST:110 U/L), respectively, without jaundice. Paracetamol was given only when there was a fever. Calcium and vitamin D supplementations were also administered.
On day 5 after zoledronic acid treatment, the AST
level decreased to 1.7 times from baseline, but not the ALT level (4.0 times
from baseline; Figure 2). The baby was then discharged from the hospital with a
plan to undergo a second zoledronic acid treatment the following month.
DISCUSSION
We reported a neonate diagnosed with OI who had
transient liver injury after zoledronic acid infusion. To the best of our
knowledge, this is the first report of hepatotoxicity following zoledronic acid
treatment in a neonate with OI. Previously, only three cases of elevated liver
enzymes induced by zoledronic acid infusion have been reported. All of them
were adult patients presenting with Paget’s disease,4 primary
osteoporosis,6 or glucocorticoid-induced
osteoporosis.5 In all
cases, the serum AST and ALT levels returned to normal after one to two weeks.
The mechanism by which bisphosphonates induce hepatic
injury has not been clearly elucidated. The acute-phase response with a febrile
reaction following bisphosphonate treatment has been described, but with an
unknown mechanism. This phenomenon cannot be explained pharmacokinetically
because half of the zoledronate will be excreted in the urine within a few
hours of administration.7 Based on an
in vivo study, IL-1, IL-6, and TNF-α
might be responsible for this reaction. After administration of a bisphosphonate,
serum IL-1 and IL-6 may be increased.8,9 Furthermore
TNF-α can stimulate macrophages to produce more IL-1 and IL-6. While IL-1
induces pyrexia, liver damage is possibly correlated with the level of TNF-α.10 We
postulated that this transient dysregulation of cytokines contributed to the
increased liver enzyme activity in our case. It is also worth noting that the Asian
population tends to have a higher incidence of acute-phase response following
zoledronic acid treatment.11
Early administration of bisphosphonates for neonates with
OI has been evaluated previously. Antoniazzi et al. found that neonates with OI
who were treated with a bisphosphonate at one month of age grew significantly
better in terms of weight and height compared to those started after the age of
six months. The incidence of fractures was also lower among those who started
bisphosphonates early. An acute-phase response with fever was common (9 out of
10 patients), but not elevated liver enzymes.12 Intravenous
bisphosphonate use is currently recommended in children with severe OI.13
Our case highlights the possibility of liver injury,
expressed by transiently increased liver enzymes, following zoledronic acid
treatment. Serum AST and ALT levels should be monitored in cases with an acute-phase
response. Although the elevated liver enzymes tend to be transient and
asymptomatic, other drugs (e.g., antibiotics) should be administered cautiously
following zoledronic acid infusion due to the risk of liver damage that can be
further aggravated. Hepatoprotective agents may be needed if the liver damage
persists.
CONCLUSION
Although hepatotoxicity is
reported to be rare, our report describes a possible adverse effect of
zoledronic acid infusion, which may be encountered in neonates treated early with
bisphosphonates. Pediatricians should pay attention to patients
with concomitant liver or systemic diseases. Baseline and subsequent liver
enzyme tests should be carried out to monitor the liver damage.
REFERENCES
1. Hackley
L, Merritt L. Osteogenesis imperfecta in the neonate. Adv neonatal care. 2008;
8(1):21–2.
2. McLean
KR. Osteogenesis imperfecta. Neonatal Netw. 2004;23(2):7–14.
3. Zeitlin
L, Rauch F, Plotkin H, Glorieux FH. Height and weight development during four
years of therapy with cyclical intravenous pamidronate in children and
adolescents with osteogenesis imperfecta types I, III, and IV. Pediatrics.
2003; 111(5 Pt 1):1030–6.
4. Polyzos
SA, Kountouras J, Anastasilakis AD, Litsas I, Kita M, Arsos G, et al.
Zoledronic acid-induced transient hepatotoxicity in a patient effectively
treated for Paget’s disease of bone. Osteoporos Int.
2011;22(1):363–7.
5. Jiang
Y, Fu Y, Xing X, Li M, Wang O, Xia W, et al. Zoledronic acid-induced
hepatotoxicity relieved after subsequent infusions in a Chinese woman
with glucocorticoid-induced osteoporosis. Eur J Med Res. 2015; 20(1):68.
6. Lu
Y, Pei Y, Shao Y, Yan S, Ma L, Fang F, et al. Hepatotoxicity induced by
zoledronic acid in an aged woman with primary osteoporosis. EXCLI J.
2013. 12: 115–7.
7. Kimmel
DB. Mechanism of action, pharmacokinetic and pharmacodynamic profile, and
clinical applications of nitrogen-containing bisphosphonates. J Dent Res.
2007; 86(11):1022–33.
8. Dicuonzo
G, Vincenzi B, Santini D, Avvisati G, Rocci L, Battistoni F, et al. Fever after
zoledronic acid administration is due to increase in TNF-alpha and IL-6. J
Interf cytokine Res. 2003; 23(11):649–54.
9. Thiébaud
D, Sauty A, Burckhardt P, Leuenberger P, Sitzler L, Green JR, et al. An in
vitro and in vivo study of cytokines in the acute-phase response
associated with bisphosphonates. Calcif Tissue Int. 1997;
61(5):386–92.
10. Schwabe
RF, Brenner DA. Mechanisms of Liver Injury. I. TNF-alpha-induced liver injury:
role of IKK, JNK, and ROS pathways. Am J Physiol Gastrointest Liver
Physiol. 2006; 290(4):G583-9.
11. Ding
Y, Zeng J-C, Yin F, Zhang C-L, Zhang Y, Li S-X, et al. Multicenter Study on
Observation of Acute-phase Responses After Infusion of Zoledronic Acid
5 mg in Chinese Women with Postmenopausal Osteoporosis. Orthop Surg. 2017;
9(3):284–9.
12. Antoniazzi
F, Zamboni G, Lauriola S, Donadi L, Adami S, Tatò L. Early bisphosphonate
treatment in infants with severe osteogenesis imperfecta. J Pediatr. 2006;
149(2):174–9.
13. Simm
PJ, Biggin A, Zacharin MR, Rodda CP, Tham E, Siafarikas A, et al. Consensus
guidelines on the use of bisphosphonate therapy in children and
adolescents. J Paediatr Child Health. 2018 ;54(3):223–33.