ORIGINAL ARTICLE
Bone Healing in Children With Osteogenesis Imperfecta
Treated With Bisphosphonates
Javier Pizones, MD,* Horacio Plotkin, MD,† Jose Ignacio Parra-Garcia, MD*
Patricia Alvarez, MD,* Pilar Gutierrez, MD,* Ana Bueno, MD,*
and Antonio Fernandez-Arroyo, MD*
Abstract: The long-term effects of bisphosphonate treatment in
children with osteogenesis imperfecta (OI) are unknown. The aim of
this study was to evaluate whether treatment with bisphosphonates
interferes with the healing of fractures in a group of children with OI.
Seven subjects (6 boys), aged 11.4 6 5.95 years, were followed for
2.5 6 0.84 years after the start of treatment with intravenous
pamidronate (9 mg/kg/y) and/or oral alendronate (5 or 10 mg/d).
Orthopaedic surgery of 24 bones was performed after 2.33 6 4.14
months of treatment, with 1.6 6 0.84 osteotomies per bone.
Ambulation was started after 26.1 6 32.28 days. Reoperation was
required in 8% of the bones due to fracture below primary fixation.
Pseudoarthrosis was seen in one fracture, an osteotomy of the
proximal femur (14% of the patients, as expected in an OI
population). These results suggest that treatment with bisphospho-
nates at the administered doses does not interfere with fracture
healing. Larger and longer studies are warranted.
Key Words: osteogenesis imperfecta, pamidronate, alendronate,
children
(J Pediatr Orthop 2005;25:332–335)
O steogenesis imperfecta (OI, brittle bone disease) is
a disease of the osteoblast.1 Due in most cases to
a mutation in the genes responsible for the production of
procollagen, the osteoblast produces an abnormal matrix that
does not respond adequately to mechanical loads. The result is
a variety of phenotypical presentations with severity that
ranges from mild forms with no fractures to forms that are
lethal in the perinatal period. Research is currently active in the
field to improve not only bone mass but more importantly bone
structure.
Treatment with calcitonin, cortisone, growth hormone,
anabolic steroids, vitamins C and D, and minerals (calcium,
From the *Orthopedic Surgery Department, Hospital Universitario de Getafe,
Madrid, Spain; and †Inherited Metabolic Diseases Section, Department of
Pediatrics, University of Nebraska Medical Center, and Children’s
Hospital Omaha, Omaha, Nebraska.
Study conducted at Hospital Universitario de Getafe, Madrid, Spain.
None of the authors received financial support for this study.
Reprints: Javier Pizones Arce, MD, Departamento de Cirugı́a, Ortopedica
Hospital Universitario de Getafe, Ctra. de Toledo Km. 12, 500, 28905
Getafe, Madrid, España (e-mail: javier.pizones@wanadoo.es).
Copyright Ó 2005 by Lippincott Williams & Wilkins
332
sodium fluoride, magnesium phosphate, and strontium) has
not been effective.2–4 Growth hormone has also been used to
increase bone mass in patients with OI but has led more to
a promotion of growth than a direct effect on mass, with no
change in cortical thickness. Some patients may even respond
negatively to this treatment with an increase in bone
resorption.5
Lower limb fractures are common in patients with OI,
inducing long periods of immobilization that cause further bone
loss.InchildrenwithOI,bisphosphonatesdecreasethisboneloss
and slow bone turnover.6,7 Bone mineral density and physical
activity increase while the fracture rate decreases and chronic
pain improves dramatically. When used in children, there are
no adverse effects on growth or bone modeling and repair.
Growth actually appears to be stimulated, suggesting that they
might have a positive effect on bone formation, and the main
effect of the drug seems to be a thickening of cortical bone.8
Bisphosphonates are currently indicated for symptom-
atic treatment of children with OI,9–11 with significant
improvement in the quality of life of the patients and without
significant side effects, although surgical correction of
deformity is still warranted. Intramedullary rods are used to
stabilize the alignment of long bones after osteotomies have
been performed,12 increasing the mechanical resistance to
impact of the long bones, aiding to avoid the natural tendency
to progressive osteoporosis and deformity, and allowing early
mobilization and weight bearing of the affected limb. Some
authors have described very early percutaneous rodding and
closed osteoclasis to obtain alignment in children with severe
deformity,13,14 while others recommend a period of physical
rehabilitation after the first fracture15 and a third group suggest
that corrective surgery would be indicated only when there is
more than 40 degrees of bowing of a long bone.16 Function
previous to surgery also affects the decision of timing and
technique.17 The current tendency favors the use of telescopic
rods. Although their use does not lack complications,18–20 it
would increase the reoperation interval for a mean of 2 to 5
years.21
The aim of the present study was to evaluate the effects
of treatment with bisphosphonates in the healing of fractures in
children with OI.
MATERIALS AND METHODS
Seven patients (six boys) with moderate to severe OI
were included in this study. Age ranged from 2 to 18 years of
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J Pediatr Orthop  Volume 25, Number 3, May/June 2005
age (mean 11.4 6 5.95 years). Six patients had type III OI and
one had type IV. All patients were evaluated and treated at the
Getafe University Hospital, Madrid, Spain.
The number of fractures sustained by the subjects before
entering the study was documented, as well as the number of
fractures during treatment with bisphosphonates (Table 1).
Traumatic and pathologic fractures and osteotomies were
grouped for the purposes of this study.
Younger patients were started on pamidronate treatment
at a dose ranging from 1.5 to 3.0 mg/kg per treatment cycle.
Dose and interval depended on age, leading to an annual dose
of 9 mg/kg/y for all subjects. Older children received
alendronate at a single daily dose of 5 mg for subjects 30
kg and under or 10 mg for subjects above 30 kg. Time during
treatment before surgery and side effects were documented for
the purposes of the study. Orthopaedic surgery was performed
based on the needs of each child, and therefore the time under
treatment before surgery varied widely. Surgery was chosen
based on the occurrence of acute fractures requiring in-
tervention, or elective surgery because of significant functional
deficit due to deformity.
The surgical technique for fixation was chosen based on
the type of fracture, presence of deformity, bone quality, and
the characteristics of each patient. These techniques included
the use of Rush intramedullary rods, Kirschner nails, and
telescopic rods (Dubow-Bailey). Information regarding the
number of osteotomies, bones corrected, and amount of blood
transfused (if any) in the operative and postsurgical periods
was documented. The timing for restart of weight bearing was
evaluated as well. Patients were evaluated immediately after
surgery and at 2 and 4 weeks, then after 3, 6, and 12 months
and annually thereafter, except in the obvious cases when
complications required more visits. In all visits the evolution
of bone healing was evaluated, and we established a limit of 6
months as a definition of delayed fracture healing.
The study was approved by the Ethics Review Board of
our institution, and all children or their legal guardians gave
written informed consent.
RESULTS
Data analysis showed that subjects sustained 3.4 6 1.2
fractures per year in the 2-year period before treatment. After
the start of treatment, the average number of fractures was
2.8 6 1.4 (P = NS). Patients had no history of nonunion
TABLE 1. Demographic Data of the Study Subjects
Fx/yr 2yr
Pat OI type Age Rx Pre-Rx
1 III 12.7 A 6
2 III 17.5 A 3
3 III 2.0 P 3
4 IV 12.6 P 2
5 III 4.9 A-P 4 3
6 III 12.1 A 3
7 III 18.0 A 3
A, Alendronate; P, Pamidronate; Fx, Fractures; Rx, Treatment.
q 2005 Lippincott Williams & Wilkins
Bisphosphonates and Bone Healing
fractures before treatment. The mean follow-up time after the
start of treatment was 2.5 6 0.84 years (range 1.1–5.4 years).
The total number of fractures in all patients under treatment
was 20. Only one fracture showed signs of nonunion after 6
months. Six subjects had a second surgery after the start of
treatment. As medical treatment, two subjects received
intravenous pamidronate only, four received oral alendronate,
and one received oral alendronate first and were switched to
intravenous pamidronate because of lack of clinical response
in terms of improvement of pain. The only side effect noted
was the well-known acute phase reaction with fever the first
time the subjects received intravenous pamidronate; this
occurred in two of the three subjects. No side effects were
noted with the use of oral alendronate.
A total of 24 bones were operated on (four re-
interventions). A detailed list of the locations and number
of osteotomies is as follows:
13 femurs (7 patients): 1.5 osteotomies (61.06) per bone
(range 0–4)
6 tibiae (4 patients): 2.3 osteotomies per bone (range 1–3)
1 humerus (1 patient): 1 osteotomy
The mean number of osteotomies was 1.6 6 0.84 per
bone. Six patients had bilateral femoral surgeries; two of them
had also both tibiae operated on. Internal fixation of the
humerus was performed using a Rush rod; for the lower limbs
the Rush rods were used in 13 cases, telescopic rods were used
in 5 cases, and Kirschner pins were placed in 2 cases.
We reoperated on four femurs in two patients (ie, 8% of
the operated bones required reoperation). Two of these
surgeries were due to fractures below the rods. In one case,
the Rush rods were replaced with longer ones after 21 months,
before a new fracture occurred. In all cases, Rush rods were
replaced with telescopic rods. An average of 1.2 6 1.0
osteotomies were performed during reoperations. Weight
bearing started a mean of 26.1 6 32.28 days after surgery.
Surgical complications included a skin infection with
Staphylococcus aureus and a case of urinary retention that
resolved after catheterization.
Radiographic controls of fractures and osteotomies were
done at 1, 3, and 6 months. In the latter, particular attention
was given to fracture healing. Only one fracture (at the level of
the proximal femur) showed signs of nonunion at this time
point (Fig. 1). The subject refused to undergo any surgical
procedures to treat this complication, and the nonunion did not
cause functional problems.
DISCUSSION
Fx Under Several bisphosphonates are currently used in children
Rx to treat different osteoporotic conditions, including OI and
5 cerebral palsy.22 Pamidronate, alendronate, and risedronate are
3 the bisphosphonates most commonly mentioned in the
3 literature. These are second-generation bisphosphonates.
1 The inhibitory effect of bisphosphonates on bone resorption
is thought to be mediated by actions on both osteoblasts23 and
1 osteoclasts.24,25 Previous reports suggested that treatment of
4 children with OI with pamidronate produces an increase in
age-corrected bone mineral density (Z score) and metacarpal
cortical thickness, and the number of radiologically confirmed
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Pizones et al
FIGURE 1. Nonunion fracture in a patient with OI after 6
months. The patient refused treatment and presented no
functional problems or pain.
fractures decreases significantly.6,11 Growth appears to happen
at the same rate or faster when compared with that of
nontreated children with OI.26
Our study in Spanish children was set up with this
background in mind. We administered intravenous pamidro-
nate and oral alendronate to patients with moderate to severe
OI and followed them for a mean of 2 years 5 months.
Corrective orthopaedic surgery was performed after a mean of
23.6 months under treatment, but some patients had surgery
immediately before the start of treatment. Side effects of the
treatment with intravenous pamidronate were transient fever
and a flulike illness attributable to an acute phase reaction in
two of the three subjects, as previously described in the
literature.11 The reduction in pain and increase in the
subjective feeling of well-being and stamina were impressive
in all subjects receiving intravenous pamidronate, as pre-
viously reported,27 and it was absent in one of the subjects
receiving oral alendronate (who then switched to intravenous
treatment with good response).
At the beginning of this study, internal fixation was
obtained using Rush rods. Two fractures occurred under the
rods after the subjects had outgrown the devices. As our
experience increased, we started placing telescopic rods, and
they are our current first choice for these growing patients. The
number of osteotomies per bone was low, with a mean of
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J Pediatr Orthop  Volume 25, Number 3, May/June 2005
1.2 6 1.0 per bone; we consider that this contributed to the
positive outcome of our patients. This was previously
described in the literature.28 We tend to use progressively
less invasive surgical techniques, performing osteotomies
through small incisions; this reduces the amount of blood loss.
Some reports suggest that there is no influence of
bisphosphonate treatment on fracture healing,29,30 whereas
others show a delay of fracture healing in animal models.31
Detrimental effects on fracture healing appeared to be dose-
related in dogs.32
The occurrence of nonunion fractures is known to be
increased in children with OI. One group identified 12
nonunions in 10 of 52 patients with OI (ie, 19% of the patients
had nonunion fractures).33 This is probably related to
decreased bone formation. In our group of patients receiving
pamidronate, only one (14%) presented with a nonunion
fracture, which is not different from what was previously
reported.
In conclusion, treatment with bisphosphonates at the
doses currently recommended for up to 5 years did not appear
to interfere with fracture healing in this small group of children
with OI.
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