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Bisphosphonates in Children

Bisphosphonates have been successfully used in adults for conditions like osteoporosis, Paget’s disease and
hypercalcaemia.
Their use in children is limited, mainly due to concerns of possible adverse effects of these drugs on a
growing skeleton,
especially as these may persist in bone for many years. In recent times bisphosphonates have been shown to
be safe in children,
at least in the short term and their use is expanding.
The conditions for which bisphosphonates have been used in children are mainly:
a) Primary defects in bone mineralization (juvenile idiopathic osteoporosis);
b) Bone matrix abnormalities (osteogenesis imperfecta);
c) Bone abnormalities secondary to systemic diseases or of iatrogenic origin;
d) Soft tissue calcifications and
e) Hypercalcaemia.
Most experience of bisphosphonates in childhood has been with the treatment of osteogenesis imperfecta.
Intravenous
Pamidronate has been shown in several studies to be beneficial and safe in these patients. Apart from
osteoporosis, other
potential uses of bisphosphonates include the treatment of dystrophic calcinosis and of chronic recurrent
multifocal
osteomyelitis (CRMO). In juvenile dermatomyositis complicated by calcinosis, bisphosphonates can reduce
calcium turnover,
deposition accretion. Moreover, their action on macrophages may reduce inflammation in the calcified
areas. These effects
could also be beneficial in other rare diseases characterized by pathological calcifications such as
fibrodysplasia ossificans
progressiva and myositis ossificans progressiva.
Increases in vertebral density and improvement in z scores are indirect measures of bone
quality & amount and arrangement of the mineral phase, but not of bone strength itself. Bisphosphonates
cause increase in
cortical thickness and the overall geometry of long bones becomes more tubular. In the bone itself, the
trabecular number — an
index of internal bone geometry, increases, but there is no change in trabecular thickness. Anecdotal reports
suggest that in
children, prolonged administration of bisphosphonates, even at subtoxic doses, makes the bones more stiff
(ie., more resistant to
bending), but more brittle (ie., less resistant to fracture). Moreover, the z scores for lumbar vertebral bone
mineral density
gradually plateau after more than two to three years of infusions.
Adverse effects in children have not been reported with increased frequency compared to adults, but the
main concern remains possible interference with bone remodeling in a growing skeleton. Observed adverse
effects include
increase in body temperature following intravenous infusion, flu-like symptoms, nausea, abdominal pain,
oesophagitis.
Reversible radiological alterations, including band like metaphyseal sclerosis and concentric epi- and
apophyseal sclerosis,
have been described in prepubertal patients. Feared, but not observed, adverse effects include irreversible
and permanent effect
on bone remodeling, impaired healing and non-union of fractures and damage to growth plates with
impairment in linear
growth. Indeed, bone biopsies of treated patients have shown no signs of mineralization defects.
There are many unanswered questions regarding bisphosphonate treatment in children. The optimum dose
and
frequency of administration and the length of treatment have not been defined. Effect on bones after
discontinuation is
unknown. The maximal bone mass gain that can be achieved is not known and it is not clear whether the
positive effects of
treatment continue over time. The criteria for initiating treatment need clarification; should treatment be
limited to children with
pre-existing low BMD and /or fractures or include children thought to be at risk of these problems? Finally,
future studies
should be longer term and include fragility fractures as an outcome. Multicentre studies are more likely to
achieve sufficient
patient numbers to answer some of these questions about longer-term treatment, including the change in
fracture incidence.
Bisphosphonates should be used with caution in children and are best reserved for clinical trials or children
with acute lytic lesions. Controlled trials should address the effect of bisphosphonates on functional
mobility and lower-limb
strength, as well as bone density, geometry, the risk of fractures, histologic features and biomechanics.
Whether predominantly
trabecular vertebral bone and cortical bone in the arms and legs have different responses
to bisphosphonates should be examined. These cautions do not preclude a role for bisphosphonates in
pediatric bone

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