J Pediatr Endocrinol Metab 2016; aop

Chanchal Kumar, Inusha Panigrahi*, Abhishek Somasekhara Aradhya, Babu Lal Meena
andNiranjan Khandelwal

Zoledronate for Osteogenesis imperfecta:

evaluation of safety profile in children
DOI 10.1515/jpem-2015-0351
Received August 31, 2015; accepted April 12, 2016
Introduction
Abstract Osteogenesis imperfecta (OI) is a clinically heterogenous
inherited disorder of bone metabolism with a prevalence
Background: The advent of bisphosphonates (BPs) has
rate of 67/100,000 at birth and is amenable to bisphos-
revolutionised the outcome of Osteogenesis imperfecta
phonate (BP) treatment to reduce the risk of fractures
(OI) in the last few years. There has always been a safety
[13]. Earlier, treatment with mainly pamidronate was
concern regarding zoledronates use due to a paucity of
available, but nowadays more potent intravenous (IV)
studies. The current study is a retrospective evaluation of
BPs like zoledronate are available, and oral BPs like
children with OI on the short- and long-term side effects of
neridronate and risedronate are also being increasingly
zoledronate and the frequency of fractures per year after
used [2, 3]. OI occurs due to defects in type 1 collagen syn-
the drug was introduced.
thesis and is characterised by bone fragility and decreased
Methods: A total of 26 children diagnosed with OI, with
bone density leading to recurrent fractures and deformi-
a median age of 84 (45121) months were enrolled in the
ties. Mutations in the COL1A1 and COL1A2 genes leading
study. They received cyclical zoledronate for a median
to qualitative and quantitative defects in type 1 collagen.
duration of 36 (1161) months at quarterly intervals
Most mutations are inherited by autosomal dominant
between January 2008 and December 2014. Safety evalua-
modes of inheritance. With the advancements in molecu-
tion involved assessment of its short- and long-term effects
lar genetics in the last decade many mutations other than
in addition to the frequency of fractures after its usage.
those in collagen genes have been identified. These are
Results: One (3%) neonate had symptomatic hypocalce-
mostly inherited in an autosomal recessive manner. These
mia 15 days after the infusion. Three children (11%) had
are usually null mutations in genes encoding proteins
acute phase reactions. None had long-term side effects,
involved either in prolyl hydroxylation (CRTAP, LEPRE1,
including osteonecrosis of the jaw, in our 7-year experi-
PPIB) or splicing (FKB10, SERPINH1) [4, 5].
ence. OI of types III and IV (total of 22) had significant
There is no definitive cure for OI. Management mainly
reductions in the number of fractures (p<0.05).
involves involves avoiding trauma and the use of BPs. The
Conclusions: Further long-duration studies are necessary
advent of BPs has revolutionised the outcome of OI in the
to evaluate the longterm safety of zoledronate.
last few years. BPs are structural analogues of pyrophos-
Keywords: bisphosphonates (BPs); bowing of bones; frac- phates. They inhibit osteoclast resorption, thereby improv-
tures; hypocalcemia; magnetic resonance imaging (MRI); ing bone density and reducing the number of fractures and
metaphyseal bands; paediatric osteoporosis; zebra lines. they are also prescribed to decrease osteoblast and osteo-
cyte apoptosis. Zoledronate, a 3rd generation BP is one of
the most potent agents available. BPs get adsorbed onto
bone surfaces and are released slowly into the bone matrix
*Corresponding author: Inusha Panigrahi, MD, DM, Additional
where they bind to hydroxyapatite and inhibit osteoclastic
Professor and Incharge, Genetic-Metabolic unit, Department of
Pediatrics, Advanced Pediatric Centre, Post Graduate Institute activity. Thus the action of BPs may last many years, even
ofMedical Education and Research, Chandigarh, India, after stopping the drug. Studies on adults have shown the
Phone: +91-7087008319, E-mail: inupan@yahoo.com action of zoledronate peaking at 1 month and persisting
Chanchal Kumar, Abhishek Somasekhara Aradhya and Babu Lal for 12months after a single IV dose [69]. Although zole-
Meena: Department of Pediatrics, Post Graduate Institute of Medical
dronate is widely used for various diseases in adults, there
Education and Research, Chandigarh, India
Niranjan Khandelwal: Department of Radio diagnosis, Post
are few studies on its usage in children. Short-term tran-
Graduate Institute of Medical Education and Research, Chandigarh, sient side effects of BPs are flu-like symptoms and hypoc-
India alcemia [10, 11]. Long-term side effects exist and include

Unauthenticated
Download Date | 6/10/16 1:37 AM
2Kumar etal.: Zoledronate for Osteogenesis imperfecta

delayed remodelling during fracture healing, decreased
longitudinal growth of long bones, renal toxicity, terato-
genicity, osteopetrosis, osteonecrosis of jaw, ocular inflam-
mation and rarely subtrochanteric fractures the femur
[12]. Therefore, there is always a safety concern regard-
ing z oledronates use among paediatricians as there are
a limited number of studies on paediatric osteoporosis.
Hence we decided to evaluate the safety of zoledronate use
in children with OI on follow-up visits in our institute.
Materials and methods
Subjects
A total of 29 children diagnosed with OI were followed in the genet-
ics clinic of a tertiary care centre in North India. Three children were
irregular on follow-ups and were excluded from the final analysis.
Infants received a dose of 2mg over 30min for two consecutive days
while children >1 year received 4mg over a similar infusion rate, i.e.
a single dose every 3 months. The infants were admitted for at least
3days during infusion and were monitored for adverse effects, while
the other children received 1 day of care (Table1).
phosphorus, alkaline phosphatase, vitamin D and in addition radi-
ological evaluation including a DEXA scan. If investigations were
suggestive of OI, they were appropriately classified based on pheno-
typic and radiological features into one of the Sillence classifications
[13, 14]. They were also classified into five types as described by the
Nosology group of the International Society for Skeletal Dysplasia
[15]. Prior to infusion, any hypocalcemia detected in ionised cal-
cium levels was corrected with IV calcium gluconate. Children were
assessed for short-term side effects like symptomatic hypocalcemia
(seizures) and acute phase reactions like fever, headache, myalgia,
flu-like illness, arthralgia, nausea, vomiting and paraesthesia up to
72h of the first, second and third cyclical zoledronate. These children
were followed-up in the genetics clinic of the institute at 3-month
intervals with monitoring of growth, number of fractures, calcium,
phosphorus, alkaline phosphatase, renal functions, 6-month DEXA
scans of the lumbar spine, and,in addition, were assessed for devel-
opment of any long-term side effects like osteonecrosis of the jaw,
ocular inflammation, delayed healing of fractures, osteopetrosis [10].
Calcium, phosphorus and alkaline phosphatase were measured by
colorimetric method. DEXA scans of lumbar spine L3L5 spines were
done during follow-up visits, using standard protocols. The evalua-
tion of OI patients is as per a pre-designed standard protocol for the
management in the subspeciality unit.
Statistics

The data were presented as mean and standard deviations (nor-

Study methods
mally distributed data) or as median and interquartile range (non-
parametric data) for continuous variables, and as frequencies and
Any child with recurrent fractures, after ruling out non-acciden- proportions for categorical variables. A normality test (Kolmogorov-
tal injury (child abuse), underwent investigations for calcium, Smirnov test) was performed with all continuous variables. Data
were compared by t-test for normally distributed continuous vari-
Table 1:Demographic parameters. ables and by Chi-square and Fishers exact tests for categorical vari-
ables. Non-parametric analysis using Wilcoxon sign rank test was
Sl no Characteristics n=29 used for continuous data that did not follow normal distribution. All
n (%) tests were two-tailed and a p-Value of <0.05 was taken as significant.
Analysis was done using statistical software packages IBM-SPSS 20
1 Total children with OI 29 version (SPSS Inc., Chicago, IL, USA).
2 OI on zoledronate therapy 26
3 Current age in months (median age) 84 (45121)
4 Male female 20:9
5 Types of OI as per Sillence classification
I 3 (10) Results
II 1 (3)
III 13 (45)
IV 10 (35)
A total of 26 children with OI were analysed for adverse
V 0 effects of zoledronate use, both its short- and long-term
VI 0 effects. Twenty-six consecutive children with OI with a
VII 1 (3) median age of 84 (45121) months received cyclical zole-
VIII 1 (3) dronate for a median duration of 36 (1161) months, with a
6 Types of OI as per Nosology
cumulative dose of 48 mg/kg (1680 mg/kg is the range),
I 3 (10)
II 1 (3) at quarterly intervals between January 2008 and Decem-
III 13 (45) ber 2014. Types III and IV were the commonest type of OI
IV 10 (35) seen in these children, predominantly in males (Table 1).
V 2 (7) Molecular analysis is under process in the institution itself.
7 Median age at diagnosis (in months) 41 (678)
We found heterozygous mutation in the COL1A2 gene by
OI, Osteogenesis imperfecta. targeted sequencing in an 8-year-old female patient with

Unauthenticated
Download Date | 6/10/16 1:37 AM
 Kumar etal.: Zoledronate for Osteogenesis imperfecta3

type IV OI as c.3304GG/T;p.G1102C. The mutation analy-
sis in other patients is underway in collaboration with the
Department of Endocrinology. The median age of onset of
fracture was 41 months (range 678 months). As all the
patients were from the paediatric age group (<12 years),
all the patients were categorised under the class of severe
variety of OI.
Three (11%) out of the 26 children had fever follow-
ing the first dose of zoledronate infusion within 72 h. Two
of them were infants <3months of age and the other was
2.5years of age. The fever was of a single spike in all three
children, with a maximum axillary temperature of 38C
and responded to oral paracetamol. None had other side
effects like nausea, headache, myalgia, flu-like symptoms
(Table2). Short-term side effects were predominantly seen
in type III OI (2/13) and 1/2 of type V (Table3).
Of the 26 children, one neonate (3%) with type III OI
had a seizure attributed to hypocalcemias onset 15days
after the first infusion of zoledronate. Ionised calcium was
low and there was no recurrence after correction. Other
workups like sugar, sepsis-meningitis evaluation and
Table 2:Safety evaluation.
cranium sonography were normal. There was no recur-
rence with subsequent doses of zolendronate. None of the
other children had any other features like Chvosteks sign/
Trousseaus sign/myalgia/paraesthesia.
Children with OI were followed-up with a median
duration of exposure of zoledronate of 36 (1161) months.
None of the children developed osteonecrosis of the jaw,
osteopetrosis, or had problems with healing of fractures,
or derangement in renal functions (Table 2).
The median number of fractures per year before zole-
dronate usage was three, whereas after drug exposure it
was reduced to one fracture per year. Types III and IV OI
(total of 22) had a significant reduction in the number of
fractures (p<0.05) (Table4).
Renal function monitoring at quarterly intervals did
not reveal any elevations of creatinine. Other side effects
like delayed healing of fractures and uveitis were not seen.
On follow-up of children with OI, X-rays of long
bones showed dense metaphyseal bands called as zebra
lines, distinct from Harris growth arrest lines. These
lines remained parallel to the growth plate and moved
towards diaphysis from metaphysis with bone growth.

Table 4:Follow-up metabolic, bone density and bone turn-over

Sl no Characteristics n=26
markers in OI.
n (%)

1 Duration of exposure of zoledronate in months 36 (1161) Sl no Characteristics (normal range) Value (%)
(3-monthly cycles)
1 Calcium (8.610.2 mg%) 9.2 (0.5)
2 Median age of zoledronate initiation after 33 (1190)
2 Inorganic phosphorus (2.74.5 mg%) 5 (0.7)
diagnosis
3 Alkaline phosphatase (40129 U/L) 215 (91)
3 Symptomatic hypocalcemia-seizures 1 (4)
4 DEXA T-scores 5.7 (0.9)
4 Fever after
1st dose 3 (11) OI, Osteogenesis imperfecta. aTotal number of OI children
2nd dose 2 (7) studied- n=26.
3rd dose 1 (4)
4th dose 0
5 Flu-like reactions, headache, vomiting, myalgia 0 A B
6 Osteonecrosis of jaw 0
7 Uveitis 0
8 Osteopetrosis, 0
9 Delayed healing of fractures 0
10 Derangement of creatinine 0

Table 3:Short-term side effects (hypocalcemia and fever) based on

the type of OI.

Sl no Types of OI n=26
n (%)

1 I 0
2 II 0
3 III 2/13a
Figure 1:Radiographs of the knee in a patient on zoledronate therapy
4 IV 0
on follow up.
5 V 1/2b
(A) X-ray of a patient on cyclical zoledronate therapy. (B)Repeat X-ray
OI, Osteogenesis imperfecta. aHypocalcemia and or fever, bfever. 6 months later shows increasing zebra lines.

Unauthenticated
Download Date | 6/10/16 1:37 AM
4Kumar etal.: Zoledronate for Osteogenesis imperfecta
Figure 1 depicts an X-ray of a distal femur of a child on
zoledronate therapy with zebra lines. On MRI evaluation
done in three patients on therapy, there was metaphy-
seal flaring and alternating bands of hyperintensity and
hypointensity reported as metaphyseal bands (Figure2).
Discussion
The current study is a retrospective analysis of the safety
profile of zoledronate in 26 children with different types
of OI, a 7-year experience from a tertiary care centre of a
developing country.
Zoledronate causes inhibition of osteoclastic activ-
ity and leads to an acute fall in calcium levels, which in
turn causes a secondary rise in parathyroid hormone. This
hypocalcaemia (biochemical) may persist for a week and
rarely can also trigger seizures [10, 11]. In the current study
hypocalcemia was seen in one neonate (3%), who had a
single episode of seizure 15 days after the infusion. This
can be overcome by treating underlying hypocalcaemia
by IV correction, especially in younger children before ini-
tiation of zoledronate infusion. The ionised calcium level
can be obtained prior to infusion. Additionally vitamin D
deficiency should also be corrected by appropriate sup-
plementation [16].
With continued use of BPs, concerns about certain
long-term effects like delayed remodelling during fracture
healing, decreased longitudinal growth of long bones,
renal toxicity, teratogenicity, osteopetrosis, osteonecro-
sis of the jaw, ocular inflammation and rarely subtro-
chanteric fractures of femur [1720] have been raised. In
the current study the average duration of therapy was
36months (range 1161 months). In the present study, no
renal abnormalities or ocular side effects were seen. Oral
BPs can have compliance problems especially in children.
BP use has been associated with osteonecrosis of the
jaw in adults due to inhibition of osteoclast resorption and
Figure 2:Saggital and coronal views of a child with Osteogenesis imperfecta showing metaphyseal flaring and metaphyseal bands.
Unauthenticated
Download Date | 6/10/16 1:37 AM
anti-angiogenic properties [21]. Hennedige etal. performed
a systematic review on the incidence of BP-(pamidronate,
zoledronate, neridronate) related osteonecrosis of jaw in
OI in children [22]. They involved four retrospective cohort
studies and one case series with a total of 501 children with
OI with mean duration of BP use of around 5 years. They
concluded that osteonecrosis of the jaw may not be caus-
ally related to BP usage in children with OI. Brown et al.
[23] did a retrospective cohort study of 37 children with
OI who received both pamidronate and zoledronate for a
mean duration of 6.5years with the mean duration of zolen-
dronate therapy being 3.3 years. Their study did not find
any association with osteonecrosis of jaw. Similarly in the
current study none had osteonecrosis due to adverse effects
of therapy even though higher doses of zolendronate were
used. When compared to adults, osteonecrosis is uncom-
mon in children and could be due to additional factors like
periodontal disease, glucocorticoid or oestrogen usage.
The G1102C variation in the exon 49 of COL1A2
detected in one child on sequencing has not been reported
in the 1000 genomes database and has been predicted to
be damaging by SIFT, Polyphen, LRT and Mutation Taster
tools (dNSFP, Houston, TX, USA). In a previous study
by Lu et al. [24], mutation in COL1A2 gene c.2314G>A(p.
Gly772Ser) substitution was identified in an adult with
complete tooth loss before puberty and history of frac-
tures. Collagen gene mutations account for most of the
cases of OI, though over ten genes have been associated
with varying phenotypic severity.
Multiple independent studies have shown improve-
ment in bone mineral density and fracture reduction rates
with BP usage [25]. Similarly controlled trials have also
shown improvement in bone density, however they failed
to demonstrate a significant reduction in fracture risk [26].
Although the current study was not primarily intended to
look into the reduction in the frequency of fractures, we
did observe a significant reduction (p<0.05).
On repeated administration of zolendronate, there can
be a cumulative accumulation of the drug and it may lead

to problems. Zebra lines are distinct from Harris growth
arrest lines seen in children receiving BPs. Each dense
line usually corresponds to an IV dose of BP and the space
between two lines represents the growth rate and delay in
the next IV dose of BP [27]. These lines are usually seen in
radiographs of distal femur and proximal tibia and they
stop after closure of physis [28, 29]. Zebra lines represent
uncoupling of bone remodelling in that primary spongiosa
persists and remodelling to secondary spongiosa does not
occur. Histological analysis of these lines has shown a
decreased proportion of calcified cartilage with increasing
distance from the growth plate and are actually the trabecu-
lae undergoing turnover [30]. However, these have not been
associated with a reduction in longitudinal growth [29]. We
also observed zebra lines in our children (Figure 1).
Overall among BPs, zoledronate is the most potent
drug available, and administration every 3 to 4 months
is easy even on a day-care basis. Except for transient
Multiple fractures
Infant Child
DDs DDs
a. Birth trauma a. Non accidental injury
b. Osteogenesis imperfecta
b. Osteogenesis imperfecta
c. Hypophosphatasia c. Rickets
d. Osteopenia of prematurity d. Copper deficiency
e. Hypophosphatemic rickets e. Rare- Scurvy
X-ray marked osteopenia, usual site
fractures, diaphyseal #
Ca, P-normal
ALP-normal/elevated
Bone turn over markers-persistently
Likely Osteogenesis imperfecta
Adequate calcium and vitamin D intake
Measure ionised calcium (normal 1-1.4 mmol/dl);
If hypocalcemia-iv calcium gluconate 1 mL/kg over 20 min
(cardiac monitoring) max 10 mL of calcium gluconate.
iv Zoledronate
2 mg in 50 mL 0.9% NS-30 min X 2 days-infant; quarterly
4 mg in 100 mL 0.9% NS over 30 min single dose- child; quarterly
Genetic counselling
Follow up
a. Quarterly Ca, P, ALP
b. Quarterly growth assessment
c. Annual lumbar spine BMD and Vitamin D levels
d. Consider growth hormone after 5 years of age,
when fracture frequency stabilised
e. MRI of selected bones and operative
intervention in those with recurrent fractures
f. Consider increase in gap between infusions
after 3 years of zoledronate
Figure 3:Management protocol followed in our institute for multi-
ple fractures.
DDs, differential diagnosis; Ca, calcium; P, phosphorus; ALP, alka-
line phosphatase; BMD, bone mineral density.
Unauthenticated
Download Date | 6/10/16 1:37 AM
Kumar etal.: Zoledronate for Osteogenesis imperfecta5
short-term side effects like hypocalcemia/flu-like symp-
toms, which can be prevented by maintaining adequate
levels of calcium and vitamin D [31]. Long-term side
effects seem to be uncommon. The management protocol
followed in our institute has been depicted in Figure 3.
Although long-term studies with large sample sizes are
necessary to evaluate long-term safety, zoledronate has
the advantage of high potency and needs only infrequent
administration. The duration of IV BPs in children and
the question of when to change to oral BPs is also a matter
of debate and requires re-evaluations.
Author contributions: Chanchal Kumar: conceptual-
ised the study, collected the data, did statistical analy-
sis and drafted the initial manuscript and approved the
final manuscript. Inusha Panigrahi: conceptualized and
designed the retrospective analysis, designed the data
collection tool, analysed the data, critically reviewed the
manuscript and approved the final manuscript. Abhishek
Somasekhara Aradhya: assisted in designing the study
and data collection, analysed the data, critically reviewed
the manuscript and approved the final manuscript. Babu
Lal Meena: assisted in designing the study and data collec-
tion, analysed the data, critically reviewed the manuscript
and approved the final manuscript. Niranjan Khandelwal:
assisted in designing the study, analysed the radiological
data, critically reviewed the manuscript and approved the
final manuscript. All the authors have accepted responsi-
bility for the entire content of this submitted manuscript
and approved submission.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played
no role in the study design; in the collection, analysis, and
interpretation of data; in the writing of the report; or in the
decision to submit the report for publication.
References
1. Brown JJ, Zacharin MR. Safety and efficacy of intravenous zole-
dronic acid in paediatric osteoporosis. J Pediatr Endocrinol Metab
2009;22:5563.
2. Barros ER, Saraiva GL, de Oliveira TP, Lazaretti-Castro M. Safety
and efficacy of a 1-year treatment with zoledronic acid compared
to pamidronate in children with osteogenesis imperfecta. J Pedi-
atr Endocrinol Metab 2012;25:48591.
3. Maines E, Monti E, Doro F, Morandi G, Cavarzere P, etal. Chil-
dren and adolescents treated with neridronate for OI show no
evidence of any osteonecrosis of the jaw. J Bone Miner Metab
2012;30:4348.
6Kumar etal.: Zoledronate for Osteogenesis imperfecta
4. Valadares ER, Carneiro TB, Santos PM, Oliveira AC, Zabel B.
What is new in genetics and osteogenesis imperfect classifica-
tion? J Pediatr (Rio J) 2014;90:53641.
5. Cole WG. The molecular pathology of osteogenesis imperfecta.
Clin Orthop Relat Res 1997;343:23548.
6. Dalle Carbonare L, Zanatta M, Gasparetto A, Valenti MT. Safety
and tolerability of zoledronic acid and other bisphospho-
nates in osteoporosis management. Drug Healthc Patient Saf
2010;2:12137.
7. Reid IR, Brown JP, Burckhardt P, Horowitz Z, Richardson P, etal.
Intravenous zoledronic acid in postmenopausal women with low
bone mineral density. N Engl J Med 2002;346:65361.
8. Plotkin LI, Weinstein RS, Parfitt AM, Roberson PK, Manolagas
SC, etal. Prevention of osteocyte and osteoblast apoptosis by
bisphosphonates and calcitonin. J Clin Invest 1999;104:136374.
9. Plotkin LI, Aguirre JI, Kousteni S, Manolagas SC, Bellido T.
Bisphosphonates and estrogens inhibit osteocyte apoptosis
via distinct molecular mechanisms downstream of extracellular
signal-regulated kinase activation. J Biol Chem 2005;280:
731725.
10. Munns CF, Rajab MH, Hong J, Briody J, Hgler W, etal. Acute
phase response and mineral status following low dose intrave-
nous zoledronic acid in children. Bone 2007;41:36670.
11. Hgler W, Yap F, Little D, Ambler G, McQuade M, etal. Short-
term safety assessment in the use of intravenous zoledronic
acid in children. J Pediatr 2004;145:7014.
12. Nicolaou N, Agrawal Y, Padman M, Fernandes JA, Bell MJ. Chang-
ing pattern of femoral fractures in osteogenesis imperfecta with
prolonged use of bisphosphonates. J Child Orthop 2012;6:217.
13. Sillence DO, Senn A, Danks DM. Genetic heterogeneity in osteo-
genesis imperfecta. J Med Genet 1979;16:10116.
14. Sillence DO. Osteogenesis imperfecta: an expanding panorama
of variants. Clin Orthop 1981;159:1125.
15. Warman ML, Cormier-Daire V, Hall C, Krakow D, Lachman R, etal.
Nosology and classification of genetic skeletal disorders: 2010
revision. Am J Med Genet A 2011;155A:94368.
16. Chennuru S, Koduri J, Bauman MA. Risk factors for symptomatic
hypocalcemia complicating treatment with zoledronic acid.
Intern Med J 2008;38:6357.
17. Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, etal.
Once-yearly zoledronic acid for treatment of postmenopausal
osteoporosis: HORIZON Pivotal Fracture Trial. N Engl J Med
2007;356:180922.
18. Hewitt RE, Lissina A, Green AE, Slay ES, Price DA, etal. The bis-
phosphonate acute phase response: rapid and copious produc-
Unauthenticated
Download Date | 6/10/16 1:37 AM
tion of proinflammatory cytokines by peripheral blood gd T cells
in response to aminobisphosphonates is inhibited by statins.
Clin Exp Immunol 2005;39:10111.
19. Bertoldo F, Pancheri S, Zenari S, Boldini S, GiovanazziB,
etal.Serum 25-hydroxyvitamin D levels modulate the
acutephase response associated with the first nitrogen
containing bisphosphonate infusion. J Bone Miner Res
2009;25:44754.
20. Meier RP, Perneger TV, Stern R, Rizzoli R, Peter RE. Increasing
occurrence of atypical femoral fractures associated with bispho-
sphonate use. Arch Intern Med 2012;172:9306.
21. Fedele S, Kumar N, Davies R, Fiske J, Greening S, etal. Dental
management of patients at risk of osteochemonecrosis of the
jaws: a critical review. Oral Dis 2009;15:52737.
22. Hennedige AH, Jayasinghe J, Khajeh J, Macfarlane TV. Systematic
review on the incidence of bisphosphonate related osteonecro-
sis of the jaw in children diagnosed with osteogenesis imper-
fecta. J Oral Maxillofac Res 2013;4:e1.
23. Brown JJ, Ramalingam L, Zacharin MR. Bisphosphonate-asso-
ciated osteonecrosis of the jaw: does it occur in children? Clin
Endocrinol (Oxf) 2008;68:8637.
24. Lu Y, Zhao F, Ren X, Li Z, Yang X, etal. A rare case of osteogen-
esis imperfecta combined with complete tooth loss. J Pediatr
Endocrinol Metab 2014;27:1437.
25. Panigrahi I, Das RR, Sharda S, Marwaha RK, Khandelwal N.
Response to zolendronic acid in children with type III osteogen-
esis imperfecta. J Bone Miner Metab 2010;28:4515.
26. Dwan K, Phillipi CA, Steiner RD, Basel D. Bisphosphonate
therapy for osteogenesis imperfecta. Cochrane Database Syst
Rev 2014;7:CD005088.
27. Renaud A, Aucourt J, Weill J, Bigot J, Dieux A, etal. Radio-
graphic features of osteogenesis imperfecta. Insights Imaging
2013;4:41729.
28. van Persijn van Meerten EL, Kroon HM, Papapoulos SE. Epi- and
metaphyseal changes in children caused by administration of
bisphosphanates. Radiology 1992;184:24954.
29. Al Muderis M, Azzopardi T, Cundy P. Zebra lines of Pamidronate
therapy in children. J Bone Joint Surg Am 2007;89A:15116.
30. Rauch F, Travers R, Plotkin H, Glorieux FH. The effects of
intravenous pamidronate on the bone tissue of children
and adolescents with osteogenesis imperfecta. J Clin Invest
2002;110:12939.
31. Drake TM, Clarke BL, Khosla S. Bisphosphonates: mecha-
nism of action and role in clinical practice. Mayo Clin Proc
2008;83:103245.