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
48. Goksen D, Coker M, Darcan S, Kose T, Kara S. Low-dose intra-
venous pamidronate treatment in osteogenesis imperfecta. Turk
J Pediatr 2007; 48: 124–29.
49. Land C, Rauch F, Glorieux FH. Cyclic intravenous pamidronate
treatment affects metaphyseal modeling in growing patients with
osteogenesis imperfecta. J Bone Miner Res 2006; 21: 374–79.
50. Vallo A, Rodriguez-Leyva F, Rodriguez-Soriano J. Osteogenesis
imperfecta: anthropometric, skeletal, and mineral metabolic
effects of long-term intravenous pamidronate therapy. Acta
Paediatr 2006; 95: 332–39.
51. Zeitlin L, Rimorac D, Travers R, Munns CFJ, Glorieux FH.
The effect of cyclical intravenous pamidronate in children and
adolescents with osteogenesis imperfecta Type V. Bone 2006;
52. Astrom E, Jorulf H, Soderhall S. Intravenous pamidronate
treatment of infants with severe osteogenesis imperfecta. Arch Dis
Child 2007; 92: 332–38.
53. Choi JH, Shin YL, Yoo HW. Short-term efficacy of monthly
pamidronate infusions in patients with osteogenesis imperfecta.
J Korean Med Sci 2007; 22: 209–12.
54. Land C, Rauch F, Travers R, Glorieux FH. Osteogenesis imper-
fecta type VI in childhood and adolescence: effects of cyclical
intravenous pamidronate treatment. Bone 2007; 40: 638–44.
55. Burke TE, Crerand SJ, Dowling F. Hypertrophic callus formation
leading to high-output cardiac failure in a patient with osteogene-
sis imperfecta. J Pediatr Orthop 1988; 8: 605–08.
56. Huaux JP, Lokietek W. Is APD a promising drug in the treatment
of severe osteogenesis imperfecta. J Pediatr Orthop 1988;
57. Devogelaer JP, Nagat de Deuxchaisnes C, Malghem J, Maldague
B. Cyclical intermittent therapy with APD in child with osteo-
genesis imperfecta: a 3 year follow-up of 7 cycles. Evidence of
fading away of the oldest radio-opaque metaphyseal bands. In:
Christiansen C, Overgaard K, eds. Osteoporosis. Aalborg:
Handelstrykkeriet Aalborg ApS, 1990: 1515–17.
58. Brumsen C, Hamdy NA, Papapoulos SE. Long-term effects of
bisphosphonates on the growing skeleton. Studies of young
patients with severe osteoporosis. Medicine (Baltimore) 1997;
59. Landsmeer-Beker EA, Massa GG, Maaswinkel-Mooy PD, van de
Kamp JJ, Papapoulos SE. Treatment of osteogenesis imperfecta
with the bisphosphonate olpadronate (dimethylaminohydroxypro-
pylidene bisphosphonate). Eur J Pediatr 1997; 156: 792–94.
60. Williams CJ, Smith RA, Ball RJ, Wilkinson H. Hypercalcaemia in
osteogenesis imperfecta treated with pamidronate. Arch Dis Child
1997; 76: 169–70.
61. Roldan EJ, Pasqualini T, Plantalech L. Bisphosphonates in
children with osteogenesis imperfecta may improve bone
mineralization but not bone strength. Report of two patients.
J Pediatr Endocrinol Metab 1999; 12: 555–59.
62. Astrom E, Soderhall S. Beneficial effect of long term intravenous
bisphosphonate treatment of osteogenesis imperfecta. Arch Dis
Child 2002; 86: 562–63.
63. Ashford RU, Dey A, Kayan K, McCloskey EV, Kanis JA. Oral
clodronate as treatment of osteogenesis imperfecta. Arch Dis Child
2003; 88: 945[Letter].
64. Davies JH, Gregory JW. Radiologic long bone appearance in a
child administered cyclical pamidronate. Arch Dis Child 2003;
88: 854. [Letter]
65. Maasalu K, Haviko T, Marston A. Treatment of children with
osteogenesis imperfecta in Estonia. Acta Paediatr 2003;
66. Montpetit K, Plotkin H, Rauch F, et al. Rapid increase in grip
force after start of pamidronate therapy in children and adoles-
cents with severe osteogenesis imperfecta. Pediatrics 2003;
67. Rauch F, Plotkin H, Zeitlin L, Glorieux FH. Bone mass, size and
density in children and adolescents with osteogenesis imperfecta:
effect of intravenous pamidronate therapy. J Bone Miner Res 2003;
68. Zeitlin L, Rauch F, Plotkin H, Glorieux FH. Height and weight
development during four years of therapy with cyclical intrave-
nous pamidronate in children and adolescents with osteogenesis
imperfecta types I, III, and IV. Pediatrics 2003; 111: 1030–36.
69. Rauch F, Travers R, Munns CFJ, Glorieux FH. Sclerotic meta-
physeal lines in a child treated with pamidronate: histomorpho-
metric analysis. J Bone Miner Res 2004; 19: 1191–93.
70. Fleming F, Woodhead HF, Briody JN, et al. Cyclic bisphospho-
nate therapy in osteogenesis imperfecta type V. J Paediatr Child
Health 2005; 41: 147–51.
71. Unal E, Abaci A, Bober E, Buyukgebiz A. Oral alendronate in
osteogenesis imperfecta. Indian Pediatr 2005; 42: 1158–60.
72. Vyskocil V, Pikner R, Kutilek S. Effect of alendronate therapy
in children with osteogenesis imperfecta. Joint Bone Spine 2005;
73. Land C, Rauch F, Munns CFJ, Sahebjam S, Glorieux FH. Verte-
bral morphometry in children and adolescents with osteogenesis
imperfecta: effect of intravenous pamidronate treatment. Bone
2006; 39: 901–06.
74. Land C, Rauch F, Montpetit K, Ruck-Gibis J, Glorieux FH.
Effect of intravenous pamidronate therapy on functional abilities
and level of ambulation in children with osteogenesis imperfecta.
J Pediatr 2006; 148: 456–60.
75. Lee DY, Cho TJ, Choi IH, et al. Clinical and radiological mani-
festations of osteogenesis imperfecta type V. J Korean Med Sci
2006; 21: 709–14.
76. Madenci E, Yilmaz K, Yilmaz M, Coskun Y. Alendronate
treatment in osteogenesis imperfecta. J Clin Rheumatol 2006;
77. Pan CH, Ma SC, Wu CT, Chen PQ. A pedicle screw fixation
technique in correcting severe kyphoscoliosis in an osteogenesis
imperfecta patient. J Spinal Disord Tech 2006; 19: 368–72.
78. Rauch F, Travers R, Glorieux FH. Pamidronate in children with
osteogenesis imperfecta: histomorphometric effects of long-term
therapy. J Clin Endocrinol Metab 2006; 91: 511–16.
79. Weber M, Roschger P, Fratzl-Zelman N, et al. Pamidronate does
not adversely affect bone intrinsic material properties in children
with osteogenesis imperfecta. Bone 2006; 39: 616–22.
80. Rauch F, Cornibert S, Cheung M, Glorieux FH. Long-bone
changes after pamidronate discontinuation in children and
adolescents with osteogenesis imperfecta. Bone 2007;
Developmental Medicine & Child Neurology 2008, 51: 17–29
81. Marini JC. Do bisphosphonates make children’s bones better or
brittle. N Engl J Med 2003; 31: 423–26.
82. Papapoulos SE, Cremers SCLM. Prolonged bisphosphonate
release after treatment in children. N Engl J Med 2007;
83. Ornoy A, Wajnberg R, Diav-Citrin O. The outcome of preg-
nancy following pre-pregnancy or early pregnancy alendronate
treatment. Reprod Toxicol 2006; 22: 578–79.
84. Munns CFJ, Rauch F, Ward L, Glorieux FH. Maternal and fetal
outcome after long-term pamidronate treatment before
conception: a report of two cases. J Bone Miner Res 2004; 19:
85. Cabar FR, Nomura RM, Zugaib M. Maternal and fetal outcome
of pamidronate treatment before conception: a case report. Clin
Exp Rheumatol 2007; 25: 344–45.