Question: In children with osteogenesis imperfecta, is daily
olpadronate therapy better than placebo in reducing fractures?
Design: Randomized (allocation concealed), blinded (clinicians,
patients, and outcome assessors), placebo-controlled trial with 2-year
follow-up.
Setting: A university medical center in Utrecht, The
Netherlands.
Patients: 34 children, 3 to 18 years of age (mean age, 10 y, 53%
girls), with osteogenesis imperfecta with restricted ambulation (maximum
walking distance, 250 m). Follow-up was complete.
Intervention: Children were allocated to a daily dosage of
olpadronate (10 mg/m2 of body weight) (n = 16) or placebo (n = 18).
All children received daily supplements of elementary calcium, 500
mg/m2 of body weight, and cholecalciferol, 400 IU.
Main outcome measures: Nonvertebral fractures, changes in bone
mineral content and bone mineral density as measured by dual-energy x-ray
absorptiometry (DXA), and functional outcome (degrees of ambulation [change of
=1 positive score point on the modified Bleck scale was considered to be a
clinically relevant improvement], maximum isometric force [abductor, grip, and
flexor strength], and self-care and mobility [pediatric disability
inventory]).
Main results: Analysis was by intention to treat. Fracture risk was
decreased in patients who received olpadronate compared with those who
received placebo (relative risk reduction, 31% [95% CI, 9 to 48]). Patients
who received olpadronate had greater increases in spinal bone mineral content
(2.24 g/y [CI, 0.20 to 4.29]) and bone mineral density (0.054 g/cm2
per y [CI, 0.012 to 0.096]) than did patients who received placebo. Groups did
not differ in terms of functional outcome. An increase in the Bleck score
occurred in 3 patients in each group.
Conclusions: In children with osteogenesis imperfecta, daily
olpadronate reduced fractures and increased bone mineral content and bone
mineral density.
The clinical and genetic heterogeneity of osteogenesis imperfecta presents
considerable challenges to the development of novel methods of treatment.
Fortunately, all of the major clinical types of osteogenesis imperfecta are
associated with abnormally high levels of formation and resorption of bone,
providing the rationale for the use of antiresorptive bisphosphonates in
osteogenesis imperfecta.
In this trial by Sakkers and colleagues, children were randomized to
receive an oral dosage of bisphosphonate or placebo each day. Although not
stated, an oral regimen, rather than the more widely used intravenous agents,
was probably more acceptable to the families. Furthermore, blinded evaluation
of the radiographs is easier with an oral regimen because cyclical doses of
intravenous bisphosphonate produce a sclerotic metaphyseal growth line that is
obvious on the radiographs.
The main finding was a reduction of the fracture risk but no improvement in
function for those who received the oral dosage of bisphosphonate for 2 years.
The study did not describe possible differences between the treatment groups
with regard to preexisting malunions and deformities, or the use of
intramedullary rods or external bracing at the time of recruitment or during
the study.
Although the oral dosage of bisphosphonate used in this study was well
tolerated by the children, 50% of the children had 1 fracture and the small
increase in bone mineral density was not accompanied by a decrease in the bone
resorption markers, suggesting that the oral dosage may have been too low.
Because only 1% to 3% of the drug is absorbed from the intestine, an increased
oral dosage may further increase the bone mineral density and reduce the bone
resorption markers, but it may also increase gastroesophageal side
effects.
Currently, bisphosphonate treatment, usually the intravenous form, is
offered to children with the moderate and severe forms of osteogenesis
imperfecta (types III and IV) or those with the mild type-I form and repeated
fractures. However, further trials are needed to answer the important
questions of whether bisphosphonates reduce the frequency of pain, scoliosis,
and basilar impression or if they improve strength, quality of life, and
longevity.