Effects of bisphosphonates in children with osteogenesis
imperfecta: an AACPDM systematic review
HEIDI CASTILLO MD1| | LISA SAMSON-FANG MD2* | | ON BEHALF OF THE AMERICAN ACADEMY FOR
CEREBRAL PALSY AND DEVELOPMENTAL MEDICINE TREATMENT OUTCOMES COMMITTEE REVIEW PANEL
1 Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. 2 University of Utah, Salt Lake City, UT, USA.
Correspondence to Lisa Samson-Fang at Department of Pediatrics, University of Utah School of Medicine, 50 North Medical Drive, Salt Lake City, UT 84132, USA.
Accepted for publication 2nd June 2008.
LIST OF ABBREVIATIONS
AACPDM American Academy for Cerebral
Palsy and Developmental Medicine
ICFInternational Classification of Func-
tioning, Disability and Health
LOELevel of evidence
Members of the American Academy for Cere-
bral Palsy and Developmental Medicine Treat-
ment Outcomes Committee Review Panel: Lisa
Samson-Fang MD, Lesly Wiart MSC PT, Laura
Vogtle PhD PT, Johanna Darrah PhD, Meg
Barry-Michaels PhD PT PCS, Robbin Hickman
PT MHSPCS, John McLaughlin MD, Lynne
Logan MA PT, Michael Msall MD, Alexander
Hoon MD, William Walker MD, Unni
This systematic review of the effects of bisphosphonate treatment in children
with osteogenesis imperfecta was conducted using the American Academy for
Cerebral Palsy and Developmental Medicine methodology for developing
systematic reviews of treatment interventions (Revision 1.1) 2004. Despite a
large body of published literature, there have been only eight studies with a
sufficiently high level of internal validity to be truly informative. These studies
confirm improvement in bone density. Many, but not all studies, demonstrate
reduction in fracture rate and enhanced growth. There has been extremely
limited evaluation of broader treatment impacts such as deformity, need for
orthopedic surgery, pain, functioning, or quality of life. Short-term side effects
were minimal. Which medication and dosing regimen is optimal and how long
patients should be treated are unclear. This body of evidence would be
strengthened by a larger controlled trial, because many studies lacked adequate
power to evaluate stated outcomes. These studies do not address the impacts of
bisphosphonates in children with milder forms of osteogenesis imperfecta and
severe forms that are not due to mutations in the type I pro-collagen gene (e.g.
types VII and VIII). Additional research is needed into treatment of infants. More
studies evaluating medication choices, optimal dosing, duration of treatment,
post-treatment impacts, and long-term side effects are necessary.
The American Academy for Cerebral Palsy and Develop-
mental Medicine (AACPDM) has undertaken the develop-
ment of systematic reviews to summarize the literature
about specific intervention strategies used to assist children
with developmental disabilities. These reviews are not
best-practice documents or practice guidelines, but rather
they gather and present the best evidence for and against
the effectiveness of an intervention. Their goal is to present
the evidence about interventions in an organized fashion to
identify gaps in evidence and help address new research
that is needed. The Academy is neither endorsing nor dis-
approving of an intervention in these reviews. Every effort
has been made to assure that AACPDM systematic reviews
are free from real or perceived bias. Details of the disclo-
sure and consensus process for AACPDM outcomes
reports can be viewed at http://www.aacpdm.org. Never-
theless, the data in an AACPDM systematic review can be
interpreted differently, depending on people’s perspectives.
Please consider the conclusions presented carefully.
BISPHOSPHONATES IN OSTEOGENESIS
Osteogenesis imperfecta (OI) represents a heterogeneous
group of conditions characterized by primary bone fragil-
ity. The incidence has been estimated at 1–2 per 20 000
births; however, milder forms of OI are probably under-
recognized. In the majority of patients, OI results from a
genetic mutation in the synthesis of type I collagen, result-
ing in deficiencies in collagen that can be quantitative (if
no protein is produced) or qualitative (if an abnormal
ª The Authors. Journal compilation ª Mac Keith Press 2008
DEVELOPMENTAL MEDICINE & CHILD NEUROLOGYREVIEW
protein is produced), or both.1These deficiencies form an
abnormal collagen matrix, creating bone fragility.2In addi-
tion, the badly formed collagen matrix is more susceptible
to the body’s normal process of repair. The amount of
bone is further reduced by osteoclastic removal of defective
collagen rods. Osteoblasts have difficulty making the
abnormal collagen and transferring it out of the cell.
Despite maximal stimulation, the osteoblasts are unable to
deliver proteins at an adequate rate, leading to a failure to
synthesize an adequate amount of bone matrix, and osteo-
Traditionally, patients with OI were classified into four
clinical subgroups using the Sillence criteria.3As our
understanding of the genotypic and phenotypic variability
has advanced, the utility of this classification has been
questioned. Some of the less common syndromes of bone
fragility, which have been historically considered to be
forms of OI, are not due to collagen defects. For example,
type VI OI is due to a mineralization defect, and Bruck
syndrome is due to an abnormality in bone specific telop-
eptidyl hydroxylase. Bone fragility syndromes (related to
mutations in type I pro-collagen or mutations in genes
encoding for proteins that modify type I pro-collagen, and
some of unknown origin) are presented in Table SI (sup-
porting information, published online).
Children with OI have clinical manifestations outside
the skeletal system (e.g. hypoacusis, dentigenesis imperfecta,
easy bruising, low muscle tone, weakness, central nervous
system complications). However, this report is focused on
the most prominent symptom, bone fragility.
No cure for OI is likely in the near future.4The variety
of mutations responsible for this condition and the difficul-
ties in control of gene expression make the possibility of
gene therapy distant. Bone marrow transplantation has
been tried in research settings with limited success.5Cur-
rently, treatment is focused on amelioration of symptoms.
Orthopedic surgery is used to strengthen long bones by
inserting telescopic rods, to minimize deformity resulting
from fractures and to treat deformities such as kyphoscoliosis.
Rehabilitation efforts include strengthening, maintaining
range, optimizing body alignment, teaching compensatory
strategies, and prescribing assistive equipment. Over the
past 50 years, various potential medical treatments to
improve bone fragility have been touted, come into vogue,
and used to treat patients, only to be found unhelpful.
These treatments have numbered more than 20, including
eight hormones, six mineral compounds, three vitamins,
and other miscellaneous treatments. In his 1981 review of
the literature, Albright noted ‘waves of interest … with a
flurry of activity focused on one medication for 20- to 30-
year periods, followed in turn by a slow shift to the next
agent.’6He also noted that many of the proposed
treatments had published research reports in which the
authors concluded a positive impact (e.g. 15 positive
reports for calcitonin, 12 for estrogen, and 14 for vitamin
D), but that no study had adequate controls. He cautioned
against continued acceptance of potential treatments with-
out adequate evaluation, including comparison with appro-
priate control populations.
In 1987 Devogelaer et al. first reported the use of a bis-
phosphonate to treat this condition.7Its use was based on a
hypothesis and extrapolated from bisphosphonate treat-
ment in other bone conditions such as juvenile osteoporosis
and Paget disease of bone. The structure of bisphos-
phonates is based on that of pyrophosphate, a naturally
occurring substance known to inhibit bone metabolism.
Bisphosphonates have evolved through time from the
original compounds (e.g. etidronate) to second- and third-
generation aminobisphosphonates such as pamidronate,
alendronate, and risedronate. These compounds inhibit
farnesyl-pyrophosphate synthase, a key enzyme in the
3-hydroxy-3-methylglutaryl-coenzyme-A reductase path-
way required for isophenylation of intracellular proteins.2
This results in failure to attach lipids to proteins that are
biological function and, in high concentrations, causing
apoptosis. The bone resorption involved in remodeling is
slowed. This results in a favoring of bone formation over
METHOD OF REVIEW
This review was conducted using the AACPDM method-
ology to developing systematic reviews of treatment inter-
ventions (revision 1.1) 2004.8
This review is limited to studies in which the intervention
was a bisphosphonate and the participants were children
(aged <18y at time of treatment) with OI defined by the
clinical features shown in Table SI. Studies that involved
other populations were included if the data for children
with OI were analyzed separately.
The literature search included PubMed (from 1950 to
April 2007), CINAHL (from 1982 to April 2007), and the
Cochrane Database of Systematic Reviews for studies pub-
lished in English. The search terms were (osteogenesis im-
perfecta AND [phosphonate OR bisphosphonate OR
pamidronate OR alendronate OR risedronate OR clodro-
nate OR etidronate OR olpadronate OR APD OR zoled-
ronic acid OR neridronate]). Reference lists in studies and
review articles and researchers knowledgeable about this
intervention were also consulted to identify potentially
Developmental Medicine & Child Neurology 2008, 51: 17–29
relevant studies. Abstracts and, if needed, full text of arti-
cles were reviewed to exclude publications that were not
reports of treatment. Of 109 citations, 70 met inclusion
Classification of the outcomes
Each study was assigned a level of evidence (LOE) ranging
from I to V, according to the study design and methods
used, and each outcome of LOE I–III studies was coded by
a component of the International Classification of Func-
tioning, Disability and Health (ICF;9Table I). LOE classi-
fications are based on a hierarchy of research designs that
range from the greatest to least according to ability of the
design alone to reduce bias.10Table II shows the hierarchy
by research design used for AACPDM reviews. Even if
a study is rated high in terms of LOE, it may still have
methodological limitations that could influence the results
of the study. Studies rated LOE I–III11–18were further
assessed for the presence or absence of these specific design
characteristics. Using the total score from this evaluation,
each study was assigned a conduct rating of strong, moder-
ate, or weak. This assessment is based on a series of ques-
tions provided in Table III. The conduct ratings of the
higher-level studies (LOE I–III)11–18are provided in
Table III so that the reader can determine the strengths
and weaknesses of each study. The findings for each out-
come of interest in all of the LOE I–III studies are
provided in Table IV categorized by component of
health.11–18Table V summarizes reported short- and long-
term complications of bisphosphonate treatment.19–54A
complete list of all relevant studies considered in this
systematic review is provided in Table SII (supporting
information published online).7,11–28,32,33,35–45,47–80
ANALYSIS AND DISCUSSION OF THE EVIDENCE
1. What evidence exists about the effects of the
bisphosphonate intervention in the component of ICF in
which it was expected to work, (body function and body
Seven outcomes about body function and structure are
available from studies with LOE I–III.11–16Changes in
bone metabolism markers were not consistent across stud-
ies. Increased bone density was documented in the spine,
femoral neck, hip (all measured by dual-energy X-ray
absorptiometry, DEXA), and tibia (measured by peripheral
changes were replicated in many studies. No changes were
seen in bone density in the calcaneus measured by ultra-
sound; however, the validity of this methodology in pediat-
rics has not been determined. Observed impacts on linear
growth were conflicting, with statistically significant posi-
tive effects on growth documented in two of five studies.
Vertebral shape improvements reached statistical signifi-
cance in one study. A reduction in non-vertebral fracture
Table I: ICF Components of health
Body function⁄body structure (BF⁄BS) Anatomical parts of the body (organs, limbs, and their components), and
physiological and psychological functions of body parts and systems
Activity & participation (A&P)Activity is the execution of a task or action by an individual
Participation is involvement in a life situation
Environmental factors (EF) Environmental factors make up the physical, social, and attitudinal
environment in which people live and conduct their lives
Source: International Classification of Functioning, Disability and Health (ICF).9
Table II: American Academy for Cerebral Palsy and Developmental
Medicine levels of evidence: hierarchy of research designs
Level Intervention (group) studies
ISystematic review of randomized controlled trials (RCTs)
Large RCT with narrow confidence intervals (n>100)
IISmaller RCT with wider confidence intervals (n<100)
Systematic review of cohort studies
Outcomes research (very large ecological studies)
III Cohort study (must have concurrent control group)
Systematic review of case–control studies
IV Case series
Cohort study without concurrent control group
(i.e. with historical control group)
V Expert opinion
Case study or report
Expert opinion based on theory or physiological research
Source: Centre for Evidence-Based Medicine.10
significant in three studies. The reduction in fracture rate
was clinically significant, ranging from 30 to 60%. There
was no significant difference between the treatment and
control groups on measures of muscle strength. Reductions
in pain and analgesic use were documented by Seikaly
et al.14but not replicated by Letocha et al.13
2. What evidence exists about the effects of
bisphosphonate intervention in the other components
Activity and participation
Positive impacts on self-care and well-being were docu-
mented by Seikaly et al.14However, other studies did not
replicate these findings. Several studies evaluated impacts
on mobility, ambulation, and functional status and found
no statistically significant change.
One study looked at the need for caregiver assistance and
found no impact.11
3. What evidence exists for linkages within and across
Several studies support linkages between changes in bone
metabolism, bone density or mineral content, and reduced
fracture risk.11One study supports a linkage between bone
density improvements, pain reduction, enhanced-self care,
4. What kinds and magnitude of medical complications
have been documented?
The many published cohort studies as well as the more
recent randomized trials allow monitoring of side effects in
a substantial number of patients. It is reassuring that very
few serious short-term side effects have been observed.
Those seen were generally mild and reversible. The most
common short-term side effects were fever and body aches
reported with first infusion. Hypocalcemia was reported in
numerous studies, but serious complications were reported
in only one study. This was a neonate who experienced sei-
zures due to hypocalcemia.31Deterioration in respiratory
function with need for intensive care support has been
observed in several infants with pre-existing respiratory
compromise.39Several authors raised concern regarding
the difficulties with intravenous access and the impact that
recurrent hospitalization might have in the functioning,
activity, and environmental-context components of health.
In one retrospective study, pamidronate treatment was
associated with delayed healing of osteotomy sites after in-
tramedullary rodding procedures.40A prospective cohort
Table III: Quality of study conduct (studies with evidence levels I–III only)
Sakkers et al.11
Gatti et al.12
Letocha et al.13
Seikaly et al.14
Antoniazzi et al.15
Rauch et al.16
DiMeglio et al.17,18
aThe quality of the study conduct is judged as strong if 6 to 7 questions are answered ‘yes’, moderate if 4 to 5 questions are answered
‘yes’, and weak if £3 questions are answered ‘yes’.
bQuestions were as follows:
1. Were inclusion and exclusion criteria of the study population well described and followed?
2. Was the intervention well described and was there adherence to the intervention assignment? (For 2-group designs, was the control
exposure also well described?)
3. Were the measures used clearly described, valid, and reliable for measuring the outcomes of interest?
4. Was the outcome assessor unaware of the intervention status of the participants (i.e. was there blind assessment)?
5. Did the authors conduct and report appropriate statistical evaluation, including power calculations?
6. Were dropouts or losses to follow-up reported, and were they less than 20%? For 2-group designs, was dropout balanced?
7. Considering the potential within the study design, were appropriate methods for controlling confounding variables and limiting
potential biases used?
cAlendronate has treatment affects for some time after discontinuation, so half of the control group may have had treatment effects
during their observation period.
Developmental Medicine & Child Neurology 2008, 51: 17–29
Table IV: Summary of studies: outcomes, measures, and results
Outcome of interestMeasure Component
A. Studies with evidence levels I–III
Sakkers et al.11(level II–strong)
Bone density DEXA, spine z-scoreBF⁄BS Increased in both groups but more so in treated
Bone density Calcaneal bone mineral content and densityBF⁄BS
No significant difference between groups
Vertebral shapeLumbar vertebral height on plain radiograph No significant difference between groups
Fracture risk Radiographically confirmed non-vertebral
31% risk reduction in treated group vs placebo
Muscle strengthHand-held myometer, shoulder abduction,
grip, hip flexion
Body⁄seated height, arm span, head
BF⁄BSNo significant difference between groups
BF⁄BS No significant difference between groups
Bone metabolism Urinary C-telopeptides, deoxypyridinolinesBF⁄BSNo significant difference between groups
Self-care and mobilityPEDIA&P No significant difference between groups
AmbulationBleck scaleA&PNo significant difference between groups
Caregiver assistancePEDI EF No significant difference between groups
Gatti et al.12(level II–moderate)
Bone density DEXA, spine, femoral neck & hipBF⁄BS Both groups improved, but pamidronate group
improved more reaching significance (p<0.05)
for lumbar spine at 6 months, and spine, femoral
neck, & hip at 12 months
Vertebral shape DEXA, projected area of lumbar vertebraeBF⁄BS Both groups improved, but pamidronate group
improved more (p<0.05)
Bone metabolismAlkaline phosphatase (total⁄bone)BF⁄BS Decreased in both groups. No statistical
Fracture rateClinical report of fracture, non-vertebral BF⁄BS Lower relative risk of any fracture during follow
up with pamidronate group (0.6, 95% confidence
GrowthHeightBF⁄BSIncreased in both groups, but more substantial
in treated group (p<0.05)
Letocha et al.13(level II–moderate)
Bone densityLumbar spine DEXA z-score BF⁄BSIncreased in treated group (p<0.001) and
unchanged in control (intergroup p<0.001)
Bone densityPeripheral quantitative computed
BF⁄BS Increases in treatment group (not significant vs
baseline but p<0.05 vs control group, who had
an average decline in z-score)
Vertebral shape Summed L1–L4 midvertebral height,
BF⁄BS Treated patients had ‘significantly greater rate of
increase than controls’ (p value not reported)
Fracture rateTime to first fractureBF⁄BSLonger in treated group but not significantly
different from control group (p=0.6)
Fracture rate Change in rate of fractures vs baseline BF⁄BSNo intergroup comparison
Gross motor functionBrief Assessment of Motor Function scale A&P
Muscle strengthLower-extremity and abdominal manual
muscle strength testing
PainNational Institutes of Health Functional
Assessment pain score
Bone metabolismBone-specific alkaline phosphatase,
osteocalcin, procallagen peptide type I
Table IV: Continued
Outcome of interestMeasure Component
Seikaly et al.14(level II–moderate)
Bone density Vertebral DEXABF⁄BS Improved in treatment phase (p<0.01)
MobilityPEDIA&P Improved in treatment and placebo phases
(difference not significant)
Self-care WeeFIMA&P More improvement in treatment phase
Well-being Not specified A&P Improved in both phases but more so during
PainNot specified BF⁄BS Reduced during treatment phase and
increased during placebo phase (p<0.001)
Pain Days per week of analgesic useBF⁄BSReduced analgesic use during treatment phase
and increased use during placebo phase
Growth⁄nutrition Body mass indexBF⁄BS
Bone metabolismuNTXReduced during treatment and placebo phases
but more so during treatment (p<0.01)
Bone metabolism Calcium, osteocalcin, PTH, dihydroxy vitamin
D, urinary hyroxyproline
Antoniazzi et al.15(level II–moderate)
Bone metabolismSerum calcium, phosphate, 25-hydroxy
vitamin D, osteocalcin, uCa⁄uCr, uNTX⁄uCR
BF⁄BS Unchanged except uCa⁄uCr, uNTX⁄uCr
declined but not significantly vs control
Insulin-like growth factor 1BF⁄BS
Increased but not significantly vs control
Recumbent length z-scoreImproved (p<0.05)
Weight z-scoreImproved (p<0.05)
Reduced (p<0.05, 2.4 vs 6.0 fractures⁄year)
Fracture rateClinically identified and radiologically
(excluded vertebral fractures and those
identified at delivery)
Bone formation Projected lumbar vertebral areaBF⁄BS
Improved but not significantly vs control
Bone painParent report, method not specifiedReduced but no statistical analysis
B. Studies evaluating discontinuation of bisphosphonates
Rauch et al.16(level III–moderate)
Bone metabolism Serum alkaline phosphatase, PTH, calcium,
vitamin D, phosphorus; uCa, uNTX
BF⁄BS Most changes not significant, except for
NTX⁄creatinine which increased off
Bone mineral contentLumbar spine DEXA BF⁄BSDecreased with treatment discontinuation,
increased with treatment continuation (p=0.04)
Fracture rateAbsolute number of clinical fractures BF⁄BSMore fractures in discontinuation group (not
Functional statusPEDI A&P No change
Mobility statusPEDI A&P
GrowthWeight z-scoreGained slightly off pamidronate (not
significant vs control)
GrowthHeight z-score BF⁄BS Declined slightly off pamidronate (not
significant vs control)
C. Studies comparing different bisphosphonates
DiMeglio et al.17(level II–weak)
Bone densityTotal body and lumber DEXABF⁄BSNo difference between groups
Developmental Medicine & Child Neurology 2008, 51: 17–29
study monitored closely and found no increase in delayed
healing compared with historical observations in patients
with OI. However, with only eight patients (24 bones sur-
geries, mean 1.6 [SD 0.84] osteotomies per bone), the
study may not be adequately powered to exclude delayed
healing as a complication.45Other short-term side effects
are listed in Table V. While osteopetrosis has been
reported in one child treated with bisphosphonates, it was
not observed in any study in which bisphosphonates were
used for treatment of OI or in any population using similar
dosing regimens.45,81The total numbers of patients across
studies is not adequate to evaluate very rare but serious side
effects such as esophagitis due to alendronate or osteone-
A small number of children were treated for up to 5
years and a few to 8 years with no reported long-term side
effects. One author suggested caution regarding the poten-
tial impact of decreased bone remodeling and increased
calcified cartilage over the long term.30,81Urinary excre-
tion of pamidronate has been documented up to 8 years
after cessation of treatment, and concerns have been raised
regarding the potential for this to affect fetal development
in previously treated pregnant women.30,82One retrospec-
tive review looked at outcomes in 24 women treated before
pregnancy or in early pregnancy with alendronate and
noted no major teratogenesis.83Biochemical analysis and
follow-up of the infants was limited. Munns et al. reported
on two infants born to women with OI who received
pamidronate before conception,84
reported on one infant.85The mothers suffered no ill
effects. In the study by Munns et al.,84both infants had
inherited OI. Neither infant had skeletal modeling
abnormalities. One infant had transient asymptomatic
and Cabar et al.
hypocalcemia at 24 hours of age (biochemical assessment
was not available on the other infant at that age), and one
infant had bilateral talipes equinovarus.
5. What is the strength of the evidence?
A large body of research exists relevant to potential impacts
of bisphosphonates in OI. The vast majority of this
research was completed with study designs that have lim-
ited internal validity. These studies have the potential to be
misleading, particularly if a systematic uncontrolled vari-
able is affecting results across all studies. Possible system-
atic confounders include the lack of blinding, lower
fracture rates with advancing age, impacts of change in care
due to study participation or time, and treatment effects of
vitamin D and calcium supplementation. While studies
with low levels of internal validity support the potential for
a treatment to have a measured impact, research with
stronger internal validity is required to confirm these
In the past 3 years, studies that have stronger internal
validity have been published with a consistent finding of
improved bone density. Reduction of fracture risk has been
demonstrated in three of four small, randomized con-
trolled trials and appears to be in the range of 30 to 60%.
The extent to which this reduction in fracture risk is clini-
cally important may depend on a particular child’s under-
lying fracture rate, the severity of the fractures, the pain
associated with the fractures, and the invasiveness of proce-
dures needed to manage those fractures. In these studies,
potential confounders remain, as the published reports did
not describe possible differences between the treatment
and control groups with regard to intramedullary rods or
external bracing at the time of recruitment or during the
Table IV: Continued
Outcome of interestMeasure Component
Linear growth Height BF⁄BS
No difference between groups
Bone metabolism Alkaline phosphatase (total & bone), uNTX,
osteocalcin, intact PTH, vitamin D
No difference between groups
Fracture incidence Radiographically confirmed fracturesBF⁄BS No difference between groups
DiMeglio and Peacock18(oral alendronate vs intravenous pamidronate)
Bone mineral density Body and lumbar spine bone mineral densityBF⁄BS
Increased similarly in both groups
Bone turnoverDecreased similarly in both groups
Fracture incidence Decreased similarly in both groups
Growth BF⁄BS Increased similarly in both groups
A&P, activity and participation; BF⁄BS, body function⁄body structure; DEXA, dual-energy X-ray absorptiometry; EF, environmental
factors; PEDI, Pediatric Evaluation of Disability Inventory; PTH, parathyroid hormone; uCa, urinary calcium; uCR, urinary creatinine; uNTX,
urinary N terminal telopeptides of type I collagen; WeeFim, functional independence measure for children.
Table V: Medical complications and adverse effects of bisphosphonates
Bishop et al.19
Bembi et al.20
Fujiwara et al.21
Astrom and Soderhall23
Transient high fever and slight lowering of serum calcium
Difficulty with intravenous access1
Restriction in social life of child⁄family due to monthly hospitalization
Glorieux et al.24
Acute-phase reaction to first infusion26
Minimal decrease in serum calcium (asymptotic)NR
Back and limb painNR
Kodama et al.25
Plotkin et al.26
Increase in fracture rate when growth hormone was added to treatment1
Acute-phase reaction with first infusion9
Mild decrease in serum calcium7
Gonzalez et al.27
Hyperthermia, nausea, vomiting, dizziness, mild abdominal pain with first
Lee et al.28
Banerjee et al.29
Transient low-grade fever with first infusion
Low serum calcium (3 patients treated with ‘calcium and vitamin D
Rauch et al.30
Decreased bone remodeling rate ‘not necessarily beneficial in the long-term,
as microdamage might accumulate in the bone tissue’
Increased calcified cartilageNR
No clinical consequences observed in study but authors felt these should be
monitored when treating patients because of potential for harm
Chien et al.31
Falk et al.32
Hypocalcemia with seizure1
Hypocalcemia without clinical symptoms during 2 of 57 treatment cycles2
Flu-like syndrome on first infusion5
Non-union at recurrent fracture site1
Grissom and Harcke33
Rauch et al.34
Transient pyrexia, nausea, joint pain NR
Short term: ionized calcium decreased in study group as a whole vs baseline
(not requiring treatment, positive Chvostek’s sign in some, no other
symptoms); drop in calcium level largest at first infusion vs later treatment
intervals; elevated parathyroid hormone with first infusion
Long term: no change in serum calcium, serum phosphorus decreased with
time initially, then stable; parathyroid hormone levels elevated in 7
Adiyaman et al.35
Arikoski et al.36
Bin-Abbas et al.37
DiMeglio et al.38
Munns et al.39
Elevated blood urea nitrogen without change in renal function or ultrasound1 of 8
Flu-like reaction with fever and muscle aches, typically with first courseMajority
Sclerotic metaphyseal bands10 of 10
Worsening respiratory status in infants with pre-existing respiratory
Munns et al.40
Delayed healing of osteotomies (relative risk 7.29, 95% confidence intervals
Zacharin and Kanumakala41
Cho et al.42
Intermittent abdominal discomfort with alendronate; only one patient
needed to discontinue treatment
6 of 16
DiMeglio et al.17
Forin et al.43
Fever, myalgias, vomitingNR
Fever with first infusion 19 of 29
Fever with subsequent infusion 5 of 29
Hypocalcemia with tremor treated with intravenous calcium in an infant1
Developmental Medicine & Child Neurology 2008, 51: 17–29
study. Additionally, the studies did not include vertebral
fractures in their calculation of fracture rate.
Positive impacts on growth, vertebral area, self-care,
well-being, and pain were seen in small numbers of
patients, but not all studies evaluating these impacts dem-
onstrated improvements. No study reported power calcula-
tions, and these small studies likely lacked adequate power
to exclude the potential for these positive impacts.
This body of evidence is exceedingly limited in the num-
ber of children evaluated in studies with LOE I–III. These
research results are based on a total of only 101 treated
individuals. The data for treatment of infants are extremely
limited, with only five treated infants compared with five
untreated infants in a randomized prospective fashion.
This body of evidence is neither robust nor comprehensive
enough to allow confident generalization to groups of
people at large. Furthermore, because studies have been
focused on children with more severe disease, this body of
research is not informative about the role of bisphospho-
nates in children with mild type I OI or other forms of OI
that are not related to collagen mutations.
SUMMARY AND DIRECTIONS FOR FUTURE
Reduction of bone fracture rate, decrease in pain, and
improvements in function and societal participation are the
stated goals in bisphosphonate treatment of children who
have OI. There have been eight studies with a sufficiently
high level of internal validity to be truly informative. These
studies confirm improvement in bone density. Many, but
not all studies, demonstrate reduction in fracture rate and
enhanced growth. Bisphosphonates do not eliminate
Table V: Continued
Gatti et al.12
Munns et al.44
Flu-like illness first infusion10 of 42
Decreased bone formation rate per bone surface 17% that of historical
Mineralized growth plate material in secondary bone
Pizones et al.45
Case series showed one case of non-union (causing no functional problems)
in seven children with a total of 20 fractures and 24 surgeries involving
1 of 7
Seikaly et al.14
Ward et al.46
Mild gastrointestinal intolerance with daily alendronate2 of 17
Single dose of alendronate resulted in:
Headache7 of 24
Nausea7 of 24
Fever5 of 24
Abdominal pain6 of 24
Symptoms more prominent with oral than intravenous administration
Antoniazzi et al.15
Febrile reaction after first infusion; despite young age at first infusion, all
infants tolerated the infusion well
9 of 10
DiMeglio and Peacock18
El Sobky et al.47
Fever, myalgia, vomiting in pamidronate group onlyNR
Fever, vomiting, transient bony aches, surgical complications similar in both
Goksen et al.48
Land et al.49
Vallo et al.50
Pyrexia and hypocalcemia after first infusion.3
Interference with periosteal resorption of unclear clinical significance
Decreased plasma calcium and inorganic phosphate in first 3 treatment days
(not requiring treatment)
Flu-like symptoms with first cycle6 of 10
Zeitlin et al.51
Acute-phase reaction after first infusionMajority
Mild hypocalcemia after first infusion
Astrom et al.52
Choi et al.53
Land et al.54
Fever after first infusion5
Fever after first infusion4
Fever and skeletal pain after first infusionMajority
Transient asymptomatic hypocalcemia, increased parathyroid hormone,
decreased serum phosphorus, and increased 25-hydroxy vitamin D
NR, not reported.
fracture risk, and they are not a cure for this disease. There
has been extremely limited evaluation of broader treatment
impacts, such as deformity, need for orthopedic surgery,
pain, functioning, or quality of life. Which medication and
dosing regimen is optimal and how long patients should be
treated are unclear. One study attempted to compare treat-
ment efficacy of different bisphosphonates (i.e. pamidro-
nate and alendronate). No difference was found, but, with
only six patients in each treated group, it is likely there was
insufficient power to detect a true difference between the
groups. Another study provided information on the post-
treatment effects of pamidronate and concluded that, at
least for 2 years after stopping medication, clinical effects
on bone density remain. The potential for causing non-
union has been a concern. One study systematically evalu-
ated this and found no increased incidence of non-union;
however, it probably lacked adequate power to exclude this
complication. Little information is available on long-term
outcomes, including side effects.
This body of evidence would be strengthened by a larger
controlled trial, because many studies lacked adequate
power to evaluate stated outcomes. Studies are needed to
evaluate the impact of bisphosphonates in individuals with
milder forms of OI and severe forms of OI that are not due
to collagen mutations (e.g. types VII and VIII). Additional
research is needed into treatment of infants. More studies
evaluating medication choices, optimal dosing, duration of
treatment, post-treatment impacts, and long-term side
effects are necessary. Ideally, these studies should be per-
formed in homogeneous groups (i.e. children of similar
ages with the same pathophysiological cause for their bone
fragility and similar levels of disease severity). Studies
should include information on potential confounders such
as intramedullary rodding and external bracing. To be
accomplished, these studies would need to be multi-
centered to allow recruitment of an adequate number of
participants. Widespread use of bisphosphonate medica-
tion is already occurring, so it may be difficult to perform a
randomized controlled trial in patients with moderate to
severe OI with an untreated control group. Study designs
assigning patients to different dosing regimens should be
considered. Given the relatively small number of pediatric
patients across studies and limited information regarding
pregnancy outcomes in women treated with bisphospho-
nates, registries to monitor for rare side effects would be
Additional Supporting Information may be found in the
online version of this article.
Table SI: Osteogenesis imperfecta (OI) and other forms of
Table SII: All studies included in the systematic review of
bisphosphonate treatments for osteogenesis imperfecta
This material is available as part of the online article
Please note: Wiley-Blackwell are not responsible for
the content or functionality of any supporting materials
supplied by the authors. Any queries (other than missing
material) should be directed to the corresponding author
for the article.
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